Non-invasive treatment of neurodegenerative diseases

ABSTRACT

Methods and devices are disclosed for the non-invasive treatment of neurodegenerative diseases through delivery of energy to target nervous tissue, particularly the vagus nerve. The devices include a magnetic stimulator having coils with toroidal windings, which are in contact with an electrically conducting medium that is adapted to conform to the contour of a target body surface of a patient. The coils induce an electric current and/or an electric field within the patient, thereby stimulating nerve fibers within the patient. The stimulation brings about reduction of neuroinflammation in patients suffering from conditions comprising Alzheimer&#39;s Disease, Parkinson&#39;s Disease, Multiple Sclerosis, postoperative cognitive dysfunction and postoperative delirium. Reduction in inflammation is effected by enhancing the anti-inflammatory competence of cytokines such as TGF-beta, wherein a retinoid or components of the retinoic acid signaling system provide an anti-inflammatory bias, by enhancing anti-inflammatory activity of a neurotrophic factor such as NGF, GDNF, BDNF, or MANF, and/or by inhibiting the activity of pro-inflammatory cytokines such as TNF-alpha.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of Ser. No. 13/005,005 filed Jan. 12,2011, which is (a) a continuation-in-part of U.S. patent applicationSer. No. 12/964,050 filed Dec. 19, 2010, which claims the benefit ofpriority of U.S. Provisional Patent Application No. 61/415,469 filedNov. 19, 2010, and (b) a continuation-in-part application of U.S. patentapplication Ser. No. 12/859,568 filed Aug. 9, 2010, which is acontinuation-in-part of U.S. patent application Ser. No. 12/408,131filed Mar. 20, 2009; each of which is incorporated herein by referencein its entirety.

BACKGROUND OF THE INVENTION

The field of the present invention relates to the delivery of energyimpulses (and/or fields) to bodily tissues for therapeutic purposes. Itrelates more specifically to the use of non-invasive methods anddevices, particularly methods that make use of magnetic stimulationdevices, to treat neurodegenerative disorders, using energy that isdelivered by such devices. The medical disorders include Alzheimer'sdisease, Parkinson's disease, multiple sclerosis, postoperativecognitive dysfunction, and postoperative delirium. The treatment relatesto stimulation of the vagus nerve to reduce neuro-inflammation, whereinpathways involving anti-inflammatory cytokines, the retinoic acidsignaling system, and/or neurotrophic factors are enhanced, and/orpathways involving pro-inflammatory cytokines are inhibited.

Treatments for various infirmities sometime require the destruction ofotherwise healthy tissue in order to produce a beneficial effect.Malfunctioning tissue is identified and then lesioned or otherwisecompromised in order to produce a beneficial outcome, rather thanattempting to repair the tissue to its normal functionality. A varietyof techniques and mechanisms have been designed to produce focusedlesions directly in target nerve tissue, but collateral damage isinevitable.

Other treatments for malfunctioning tissue can be medicinal in nature,but in many cases the patients become dependent upon artificiallysynthesized chemicals. In many cases, these medicinal approaches haveside effects that are either unknown or quite significant.Unfortunately, the beneficial outcomes of surgery and medicines areoften realized at the cost of function of other tissues, or risks ofside effects.

The use of electrical stimulation for treatment of medical conditionshas been well known in the art for nearly two thousand years. It hasbeen recognized that electrical stimulation of the brain and/or theperipheral nervous system and/or direct stimulation of themalfunctioning tissue holds significant promise for the treatment ofmany ailments, because such stimulation is generally a wholly reversibleand non-destructive treatment.

Nerve stimulation is thought to be accomplished directly or indirectlyby depolarizing a nerve membrane, causing the discharge of an actionpotential; or by hyperpolarization of a nerve membrane, preventing thedischarge of an action potential. Such stimulation may occur afterelectrical energy, or also other forms of energy, are transmitted to thevicinity of a nerve [F. RATTAY. The basic mechanism for the electricalstimulation of the nervous system. Neuroscience Vol. 89, No. 2, pp.335-346, 1999; Thomas HEIMBURG and Andrew D. Jackson. On solitonpropagation in biomembranes and nerves. PNAS vol. 102 (no. 28, Jul. 12,2005): 9790-9795]. Nerve stimulation may be measured directly as anincrease, decrease, or modulation of the activity of nerve fibers, or itmay be inferred from the physiological effects that follow thetransmission of energy to the nerve fibers.

Electrical stimulation of the brain with implanted electrodes has beenapproved for use in the treatment of various conditions, includingmovement disorders such as essential tremor and Parkinson's disease. Theprinciple underlying these approaches involves disruption and modulationof hyperactive neuronal circuit transmission at specific sites in thebrain. Unlike potentially dangerous lesioning procedures in whichaberrant portions of the brain are physically destroyed, electricalstimulation is achieved by implanting electrodes at these sites. Theelectrodes are used first to sense aberrant electrical signals and thento send electrical pulses to locally disrupt pathological neuronaltransmission, driving it back into the normal range of activity. Theseelectrical stimulation procedures, while invasive, are generallyconducted with the patient conscious and a participant in the surgery.

Brain stimulation, and deep brain stimulation in particular, is notwithout some drawbacks. The procedure requires penetrating the skull,and inserting an electrode into brain matter using a catheter-shapedlead, or the like. While monitoring the patient's condition (such astremor activity, etc.), the position of the electrode is adjusted toachieve significant therapeutic potential. Next, adjustments are made tothe electrical stimulus signals, such as frequency, periodicity,voltage, current, etc., again to achieve therapeutic results. Theelectrode is then permanently implanted, and wires are directed from theelectrode to the site of a surgically implanted pacemaker. The pacemakerprovides the electrical stimulus signals to the electrode to maintainthe therapeutic effect. While the therapeutic results of deep brainstimulation are promising, there are significant complications thatarise from the implantation procedure, including stroke induced bydamage to surrounding tissues and the neuro-vasculature.

One of the most successful applications of modern understanding of theelectrophysiological relationship between muscle and nerves is thecardiac pacemaker. Although origins of the cardiac pacemaker extend backinto the 1800's, it was not until 1950 that the first practical, albeitexternal and bulky, pacemaker was developed. The first truly functional,wearable pacemaker appeared in 1957, and in 1960, the first fullyimplantable pacemaker was developed.

Around this time, it was also found that electrical leads could beconnected to the heart through veins, which eliminated the need to openthe chest cavity and attach the lead to the heart wall. In 1975 theintroduction of the lithium-iodide battery prolonged the battery life ofa pacemaker from a few months to more than a decade. The modernpacemaker can treat a variety of different signaling pathologies in thecardiac muscle, and can serve as a defibrillator as well (see U.S. Pat.No. 6,738,667 to DENO, et al., the disclosure of which is incorporatedherein by reference).

Another application of electrical stimulation of nerves has been thetreatment of radiating pain in the lower extremities by stimulating thesacral nerve roots at the bottom of the spinal cord (see U.S. Pat. No.6,871,099 to WHITEHURST, et al., the disclosure of which is incorporatedherein by reference).

Yet another application of electrical stimulation of nerves has been thetreatment of epilepsy and depression by vagus nerve stimulation (VNS)[U.S. Pat. No. 4,702,254 entitled Neurocybernetic prosthesis, to ZABARA;U56341236 entitled Vagal nerve stimulation techniques for treatment ofepileptic seizures, to OSORIO et al; US5299569 entitled Treatment ofneuropsychiatric disorders by nerve stimulation, to WERNICKE et al]. Forthis procedure, the left vagus nerve is ordinarily stimulated at alocation on the neck by first implanting an electrode there, thenconnecting the electrode to an electrical stimulator.

Despite the clinical success of VNS in treating epilepsy and depression,a specific mechanism underlying VNS relief of symptoms is not currentlyknown. Vagus afferent fibers innervate several medullary structures;with the nucleus of the tractus solitarius (NTS) receiving bilateralinputs totaling approximately eighty percent of all vagal afferents. TheNTS has widespread projections, including direct or multiple synapticprojections to the parabrachial nucleus, vermis, inferior cerebellarhemispheres, raphe nuclei, periaquaductal gray, locus coeruleus,thalamus, hypothalamus, amygdala, nucleus accumbens, anterior insula,infralimbic cortex, and lateral prefrontal cortex, making it difficultto determine the area or neuronal pathway mediating VNS effects.However, functional imaging studies have concluded that VNS may bringabout changes in several areas of the brain, including the thalamus,cerebellum, orbitofrontal cortex, limbic system, hypothalamus, andmedulla. The stimulation of particular areas of the brain has beensuggested as a mechanism for the effects of VNS, but such localizedstimulation of the brain may depend upon the parameters of thestimulation (current, frequency, pulse width, duty cycle, etc.). Thoseparameters may also determine which neurotransmitters are modulated(including norepinephrine, seratonin, and GABA) [Mark S. George, ZiadNahas, Daryl E. Bohning, Qiwen Mu, F. Andrew Kozel, Jeffrey Borckhardt,Stewart Denslow. Mechanisms of action of vagus nerve stimulation (VNS).Clinical Neuroscience Research 4 (2004) 71-79; Jeong-Ho Chae, ZiadNahas, Mikhail Lomarev, Stewart Denslow, Jeffrey P. Lorberbaum, Daryl E.Bohning, Mark S. George. A review of functional neuroimaging studies ofvagus nerve stimulation (VNS). Journal of Psychiatric Research 37 (2003)443-455; G. C. Albert, C. M. Cook, F. S. Prato, A. W. Thomas. Deep brainstimulation, vagal nerve stimulation and transcranial stimulation: Anoverview of stimulation parameters and neurotransmitter release.Neuroscience and Biobehavioral Reviews 33 (2009) 1042-1060; GROVES DA,Brown V J. Vagal nerve stimulation: a review of its applications andpotential mechanisms that mediate its clinical effects. NeurosciBiobehav Rev (2005) 29:493-500; Reese TERRY, Jr. Vagus nervestimulation: a proven therapy for treatment of epilepsy strives toimprove efficacy and expand applications. Conf Proc IEEE Eng Med BiolSoc. 2009; 2009:4631-4].

To date, the selection of stimulation parameters for VNS has been highlyempirical, in which the parameters are varied about some initiallysuccessful set of parameters, in an effort to find an improved set ofparameters for each patient. A more efficient approach to selectingstimulation parameters might be to select a stimulation waveform thatmimics electrical activity in the region of the brain that one isattempting to stimulate, in an effort to entrain the naturally occurringelectrical waveform, as suggested in U.S. Pat. No. 6,234,953, entitledElectrotherapy device using low frequency magnetic pulses, to THOMAS etal. and application number US20090299435, entitled Systems and methodsfor enhancing or affecting neural stimulation efficiency and/orefficacy, to GLINER et al.

The present disclosure involves devices and medical procedures thatstimulate nerves by transmitting energy to nerves and tissuenon-invasively. A medical procedure is defined as being non-invasivewhen no break in the skin (or other surface of the body, such as a woundbed) is created through use of the method, and when there is no contactwith an internal body cavity beyond a body orifice (e.g., beyond themouth or beyond the external auditory meatus of the ear). Suchnon-invasive procedures are distinguished from invasive procedures(including minimally invasive procedures) in that invasive procedures doinvolve inserting a substance or device into or through the skin or intoan internal body cavity beyond a body orifice.

Potential advantages of such non-invasive medical methods and devicesrelative to comparable invasive procedures are as follows. The patientmay be more psychologically prepared to experience a procedure that isnon-invasive and may therefore be more cooperative, resulting in abetter outcome. Non-invasive procedures may avoid damage of biologicaltissues, such as that due to bleeding, infection, skin or internal organinjury, blood vessel injury, and vein or lung blood clotting.Non-invasive procedures are sometimes painless or only minimally painfuland may be performed without the need for even local anesthesia. Lesstraining may be required for use of non-invasive procedures by medicalprofessionals. In view of the reduced risk ordinarily associated withnon-invasive procedures, some such procedures may be suitable for use bythe patient or family members at home or by first-responders at home orat a workplace, and the cost of non-invasive procedures may be reducedrelative to comparable invasive procedures.

For example, transcutaneous electrical nerve stimulation (TENS) isnon-invasive because it involves attaching electrodes to the surface ofthe skin (or using a form-fitting conductive garment) without breakingthe skin. In contrast, percutaneous electrical stimulation of a nerve isminimally invasive because it involves the introduction of an electrodeunder the skin, via needle-puncture of the skin. Both TENS andpercutaneous electrical stimulation can be to some extent unpleasant orpainful, in the experience of patients that undergo such procedures. Inthe case of TENS, as the depth of penetration of the stimulus under theskin is increased, any pain will generally begin or increase.

Neurodegenerative diseases result from the deterioration of neurons,causing brain dysfunction. The diseases are loosely divided into twogroups—conditions affecting memory that are ordinarily related todementia and conditions causing problems with movements. The most widelyknown neurodegenerative diseases include Alzheimer (or Alzheimer's)disease and its precursor mild cognitive impairment (MCI), Parkinson'sdisease (including Parkinson's disease dementia), and multiplesclerosis.

Less well-known neurodegenerative diseases include adrenoleukodystrophy,AIDS dementia complex, Alexander disease, Alper's disease, amyotrophiclateral sclerosis (ALS), ataxia telangiectasia, Batten disease, bovinespongiform encephalopathy, Canavan disease, cerebral amyloid angiopathy,cerebellar ataxia, Cockayne syndrome, corticobasal degeneration,Creutzfeldt-Jakob disease, diffuse myelinoclastic sclerosis, fatalfamilial insomnia, Fazio-Londe disease, Friedreich's ataxia,frontotemporal dementia or lobar degeneration, hereditary spasticparaplegia, Huntington disease, Kennedy's disease, Krabbe disease, Lewybody dementia, Lyme disease, Machado-Joseph disease, motor neurondisease, Multiple systems atrophy, neuroacanthocytosis, Niemann-Pickdisease, Pelizaeus-Merzbacher Disease, Pick's disease, primary lateralsclerosis including its juvenile form, progressive bulbar palsy,progressive supranuclear palsy, Refsum's disease including its infantileform, Sandhoff disease, Schilder's disease, spinal muscular atrophy,spinocerebellar ataxia, Steele-Richardson-Olszewski disease, subacutecombined degeneration of the spinal cord, survival motor neuron spinalmuscular atrophy, Tabes dorsalis, Tay-Sachs disease, toxicencephalopathy, transmissible spongiform encephalopathy, Vasculardementia, and X-linked spinal muscular atrophy, as well as idiopathic orcryptogenic diseases as follows: synucleinopathy, progranulinopathy,tauopathy, amyloid disease, prion disease, protein aggregation disease,and movement disorder. A more comprehensive listing may be found at theweb site (www) of the National Institute of Neurological Disorders andStroke (ninds) of the National Institutes of Health (nih) of the UnitedStates government (gov) in a subdirectory (/disorder/disorder_index) webpage (htm). It is understood that such diseases often go by more thanone name and that a nosology may oversimplify pathologies that occur incombination or that are not archetypical.

Certain other disorders, such as postoperative cognitive dysfunctionhave been described only recently, and they too may involveneuro-degeneration. Other disorders such as epilepsy may not beprimarily neurodegenerative, but at some point in their progression theymight involve nerve degeneration.

Despite the fact that at least some aspect of the pathology of each ofthe neurodegenerative diseases mentioned above is different from theother diseases, their pathologies ordinarily share other features, sothat they may be considered as a group. Furthermore, aspects of theirpathologies that they have in common often make it possible to treatthem with similar therapeutic methods. Thus, many publications describefeatures that neurodegenerative diseases have in common [Dale E.Bredesen, Rammohan V. Rao and Patrick Mehlen. Cell death in the nervoussystem. Nature 443 (2006): 796-802; Christian Haass. Initiation andpropagation of neurodegeneration. Nature Medicine 16(11, 2010):1201-1204; Eng H Lo. Degeneration and repair in central nervous systemdisease. Nature Medicine 16(11, 2010):1205-1209; Daniel M. Skovronsky,Virginia M.-Y. Lee, and John Q. Trojanowski. Neurodegenerative Diseases:New Concepts of Pathogenesis and Their Therapeutic Implications. Annu.Rev. Pathol. Mech. Dis. 1 (2006): 151-70; Michael T. Lin and M. FlintBeal. Mitochondrial dysfunction and oxidative stress inneurodegenerative diseases. Nature 443 (2006): 787-795; Jorge J. Palop,Jeannie Chin and Lennart Mucke. A network dysfunction perspective onneurodegenerative diseases. Nature 443 (2006): 768-773; David C.Rubinsztein. The roles of intracellular protein-degradation pathways inneurodegeneration. Nature 443 (2006): 780-786].

One such common feature is the presence of inflammation, wherein thebody recognizes the abnormality of the relevant neuronal tissue andresponds to minimize or repair the effects of the abnormality and/oreventually destroy the abnormal tissue. [Sandra Amor, Fabiola Puentes,David Baker and Paul van der Valk. Inflammation in neurodegenerativediseases. Immunology, 129 (2010), 154-169; Mark H. DeLegge.Neurodegeneration and Inflammation. Nutrition in Clinical Practice 23(2008):35-41; Tamy C Frank-Cannon, Laura T Alto, Fiona E McAlpine andMalù G Tansey. Does neuroinflammation fan the flame in neurodegenerativediseases? Molecular Neurodegeneration 2009, 4:47-59; Christopher K.Glass, Kaoru Saijo, Beate Winner, Maria Carolina Marchetto, and Fred H.Gage. Mechanisms Underlying Inflammation in Neurodegeneration. Cell 140(2010): 918-934; V. Hugh Perry. The influence of systemic inflammationon inflammation in the brain: implications for chronic neurodegenerativedisease. Brain, Behavior, and Immunity 18 (2004): 407-413; MarianneSchultzberg, Catharina Lindberg, Åsa Forslin Aronsson, Erik Hjorth,Stefan D. Spulber, Mircea Oprica. Inflammation in the nervoussystem—Physiological and pathophysiological aspects. Physiology &Behavior 92 (2007) 121-128; Frauke Zipp and Orhan Aktas. The brain as atarget of inflammation: common pathways link inflammatory andneurodegenerative diseases. Trends in Neurosciences 29 (9, 2006)518-527]. It is understood that inflammation may accompany not onlyneurodegenerative disease, but also brain injury that is caused, forexample, by trauma, stroke, or infection. Consequently, the methods thatare disclosed herein may also be applicable to any situation in whichinflammation in the central nervous system presents a danger to thepatient.

Because excessive and prolonged inflammation may destroy nervous tissuethat is associated with neurodegenerative diseases, therapies have beenproposed to prevent, reduce, or eliminate the immune response in suchinflammation, or to repair damage that may have been produced byinflammation. Inflammation is modulated by cytokines, which are smallcell-signaling protein or peptide molecules that are secreted by glialcells of the nervous system, by numerous cells of the immune system, andby many other cell types. Some cytokines may regarded as hormones, butin what follows, the term cytokine is used to refer to any of thoseimmuno-modulating molecules, with the understanding that they may alsoparticipate in pathways other than immunomodulation.

In general, one may adopt two approaches to reduce or preventinflammation that is modulated by cytokines. First, one may attempt toinhibit the release or effectiveness of cytokines that promoteinflammation. Those cytokines are called pro-inflammatory, and the firstapproach is essentially an anti-pro-inflammatory strategy. Becausepro-inflammatory cytokines may promote the release of otherpro-inflammatory cytokines, the goal is especially to inhibit therelease of the initially released pro-inflammatory cytokines in aninflammatory cascade. For example, the cytokine tumor necrosis factor(TNF-alpha) is considered to be a pro-inflammatory cytokine of centralimportance, and anti-TNF-alpha strategies seek to inhibit the release oreffectiveness of TNF-alpha that is released from immune and other cells[Ian A. Clark, Lisa M. Alleva, Bryce Vissel. The roles of TNF in braindysfunction and disease. Pharmacology & Therapeutics 128 (2010):519-548; Melissa K McCoy and Malú G Tansey. TNF signaling inhibition inthe CNS: implications for normal brain function and neurodegenerativedisease. Journal of Neuroinflammation 2008, 5:45].

A second approach to reducing inflammation that is modulated bycytokines is to enhance and/or stimulate the release or effectiveness ofcytokines that inhibit inflammation. Those cytokines are calledanti-inflammatory, and the second approach is essentially apro-anti-inflammatory strategy. As indicated below,pro-anti-inflammatory mechanisms are often associated with the repair oftissue, which may correspond in the adult to mechanisms that were usedin the embryo to create tissue originally. The cytokine transforminggrowth factor beta (TGF-beta) is often regarded as anti-inflammatory,but as described presently, its anti-inflammatory capabilities arecontingent upon certain conditions being met. According to the secondapproach, one endeavors to promote such conditions, as well as topromote the release of, for example, TGF-beta into a potentiallyinflammatory environment.

In a series of publications, patents, and patent applications, Kevin J.TRACEY and colleagues described electrical stimulation of the vagusnerve in an attempt to effect the first, anti-pro-inflammatory strategy[Kevin J. Tracey. The inflammatory reflex. Nature 420 (2002): 853-859;Kevin J. Tracey. Physiology and immunology of the cholinergicanti-inflammatory pathway. J. Clin. Invest. 117 (2007): 289-296; KevinJ. Tracey. Understanding immunity requires more than immunology. NatureImmunology 11 (2010): 561-564; G. R. Johnston and N. R. Webster.Cytokines and the immunomodulatory function of the vagus nerve. BritishJournal of Anaesthesia 102(4, 2009): 453-462]. U.S. Pat. No. 6,610,713and U.S. Pat. No. 6,838,471, entitled Inhibition of inflammatorycytokine production by cholinergic agonists and vagus nerve stimulation,to TRACEY, mention treatment of neurodegenerative diseases within a longlist of diseases, in connection with the treatment of inflammationthrough stimulation of the vagus nerve. According to those patents,“Inflammation and other deleterious conditions . . . are often inducedby proinflammatory cytokines, such as tumor necrosis factor (TNF; alsoknown as TNF.alpha. or cachectin) . . . ” The patents go on to statethat “Proinflammatory cytokines are to be distinguished fromanti-inflammatory cytokines, . . . , which are not mediators ofinflammation.” It is clear from those patents that the objective ofTRACEY and colleagues is only to suppress the release of proinflammatorycytokines, such as TNF-alpha. There is no mention or suggestion that themethod is intended to modulate the activity of anti-inflammatorycytokines, and in fact, the text quoted above disclaims a role foranti-inflammatory cytokines as mediators of inflammation. Those patentsand applications make a generally unjustified dichotomy between pro- andanti-inflammatory cytokines, by suggesting that a cytokine could be oneor the other, but not both. In particular, the patents make no mentionof the cytokine TGF-beta, and there is no suggestion that the role of acytokine in regards to its pro- or anti-inflammation competence may beinherently indeterminate or indefinite unless more information isprovided about the presumed physiological environment in which thecytokine finds itself.

Treatment of neurodegenerative diseases is also mentioned within longlists of diseases in the following related applications to TRACEY andhis colleague HUSTON, wherein stimulation of the vagus nerve is intendedto suppress the release of proinflammatory cytokines such as TNF-alpha:US20060178703, entitled Treating inflammatory disorders by electricalvagus nerve stimulation, to HUSTON et al.; US20050125044, entitledInhibition of inflammatory cytokine production by cholinergic agonistsand vagus nerve stimulation, to TRACEY; US20080249439, entitledTreatment of inflammation by non-invasive stimulation to TRACEY et al.;US20090143831, entitled Treating inflammatory disorders by stimulationof the cholinergic anti-inflammatory pathway, to HUSTON et al; US20090248097, entitled Inhibition of inflammatory cytokine production bycholinergic agonists and vagus nerve stimulation, to TRACEY et al. Thesame observations made above in connection with U.S. Pat. No. 6,610,713and U.S. Pat. No. 6,838,471 apply to those applications as well.

SUMMARY OF THE INVENTION

The present invention discloses methods and devices for the non-invasivetreatment of neurodegenerative conditions, utilizing an energy sourcethat transmits energy non-invasively to nervous tissue. In particular,the devices can transmit energy to, or in close proximity to, a vagusnerve of the patient, in order to temporarily stimulate, block and/ormodulate electrophysiological signals in that nerve. Theneurodegenerative conditions, disorders or diseases that can be treatedwith the present invention include Alzheimer's disease, Parkinson'sdisease, multiple sclerosis, postoperative cognitive dysfunction orpostoperative delirium.

In one aspect of the invention, a method for treating aneurodegenerative disorder in a patient comprises applying energytranscustaneously through an outer skin surface of the patient togenerate an electrical impulse at or near a selected nerve, such as thevagus nerve, within the patient. The electrical impulse is sufficient toinhibit inflammation in the patient and treat the neurodegenerativedisorder. In some embodiments, the electrical impulse is sufficient toinhibit and/or block the release of pro-inflammatory cytokines, such asTNF-alpha. In other embodiments, the electrical impulse is sufficient toincrease the anti-inflammatory competence of certain cytokines tothereby offset or reduce the effect of pro-inflammatory cytokines.

In one embodiment, an electrical current is transcutaneously appliedthrough the outer skin surface of the patient to the vagus nerve. Inanother embodiment, a magnetic field is generated exterior to thepatient that is sufficient to induce an electrical impulse at or nearthe selected nerve (e.g., the vagus nerve) within the patient.

In a preferred embodiment, a time-varying magnetic field is generatedwithin an enclosed coil outside of the patient that induces anelectrical field. The electrical field is shaped such that an electricalcurrent is conducted through the outer skin surface of the patient tomodulate the selected nerve. The electrical field may be shaped bygenerating a second time-varying magnetic field within a second enclosedcoil positioned near or adjacent to the first enclosed coil. In otherembodiments, the electrical field may be shaped by positioning aconducting medium around a portion of the enclosed coil such that thedirection of the electrical field is constrained within the conductingmedium.

In another aspect of the invention, an apparatus for applying energytranscutaneously to a target region within a patient with aneurodegenerative disorder is provided. The apparatus includes a sourceof energy for generating an energy field that is located essentiallyentirely exterior to an outer skin surface of the patient. The energyfield is sufficient to transcutaneously pass through the outer skinsurface and generate an electrical impulse at or near the target region.The electrical impulse modulates activity of a selected nerve at thetarget region to inhibit inflammation in the patient and treat theneurodegenerative disorder. The apparatus preferably also includes aconduction medium that electrically couples the electric field with theouter skin surface to facilitate passage of the electric currenttherethrough.

In an exemplary embodiment, a magnetic stimulator is used to modulateelectrical activity of the vagus nerve. The stimulator comprises asource of electrical power, a magnetically permeable toroidal core, anda coil that is wound around the core. The device also comprises acontinuous electrically conducting medium with which the coil and coreare in contact, wherein the conducting medium has a shape that conformsto the contour of a target body surface of a patient when the medium isapplied to the target body surface. For the present medicalapplications, the device is ordinarily applied to the patient's neck.The source of power supplies a pulse of electric charge to the coil,such that the coil induces an electric current and/or an electric fieldwithin the patient. The stimulator is configured to induce a peak pulsevoltage sufficient to produce an electric field in the vicinity of anerve such as the vagus, to cause the nerve to depolarize and reach athreshold for action potential propagation. By way of example, thethreshold electric field for stimulation of nerve terminals may be about8 V/m at 1000 Hz. For example, the device may induce an electric fieldwithin the patient of about 10 to 600 V/m and an electrical field with agradient of greater than 2 V/m/mm.

The preferred magnetic stimulator comprises two toroidal coils andcorresponding cores that lie side-by-side, each containing ahigh-permeability material, wherein current passing through a coilproduces a magnetic field within the core of about 0.1 to 2 Tesla.Current passing through a coil may be about 0.5 to 20 amperes, typically2 amperes, with voltages across each coil of 10 to 100 volts. Thecurrent is passed through the coils in bursts of pulses. The burstrepeats at 1 Hz to 5000 Hz, preferably at 15-50 Hz. The pulses haveduration of 20 to 1000 microseconds, preferably 200 microseconds andthere may be 1 to 20 pulses per burst. The preferred magnetic stimulatorshapes an elongated electric field of effect that can be orientedparallel to a long nerve, such as the vagus nerve.

By selecting a suitable waveform to stimulate the nerve, the magneticstimulator produces a correspondingly selective physiological responsein an individual patient. In general, the induced electrical signal hasa frequency between about 1 Hz to 3000 Hz and a pulse duration ofbetween about 10-1000 microseconds. By way of example, at least oneinduced electrical signal may be of a frequency between about 15 Hz to35 Hz. By way of example, at least one induced electrical signal mayhave a pulsed on-time of between about 50 to 1000 microseconds, such asbetween about 100 to 300 microseconds. The induced electrical signal mayhave any desired waveform, which may comprise one or more of: a full orpartial sinusoid, a square wave, a rectangular wave, and triangle wave.

Teachings of the present invention demonstrate how non-invasivestimulators may be positioned and used against body surfaces,particularly at a location on the patient's neck under which the vagusnerve is situated. Those teachings also provide methods for treatment ofparticular neurodegenerative diseases that involve neurodegeneration,neuroinflammation, or inflammation more generally. However, it should beunderstood that application of the methods and devices is not limited tothe examples that are given.

Stimulation of the vagus nerve with the magnetic stimulator brings aboutreduction of neuroinflammation in patients suffering from conditionscomprising Alzheimer's Disease, Parkinson's Disease, Multiple Sclerosis,postoperative cognitive dysfunction and postoperative delirium. Thereduction in inflammation is effected by enhancing the anti-inflammatorycompetence of cytokines such as TGF-beta, wherein a retinoid orcomponents of the retinoic acid signaling system provide ananti-inflammatory bias; by enhancing anti-inflammatory activity of aneurotrophic factor such as NGF, GDNF, BDNF, or MANE; and/or byinhibiting the activity of pro-inflammatory cytokines such as TNF-alpha.

The novel systems, devices and methods for treating medical conditionsusing the disclosed magnetic stimulator or other non-invasivestimulation devices are more completely described in the followingdetailed description of the invention, with reference to the drawingsprovided herewith, and in claims appended hereto. Other aspects,features, advantages, etc. will become apparent to one skilled in theart when the description of the invention herein is taken in conjunctionwith the accompanying drawings.

INCORPORATION BY REFERENCE

Hereby, all issued patents, published patent applications, andnon-patent publications that are mentioned in this specification areherein incorporated by reference in their entirety for all purposes, tothe same extent as if each individual issued patent, published patentapplication, or non-patent publication were specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purposes of illustrating the various aspects of the invention,there are shown in the drawings forms that are presently preferred, itbeing understood, however, that the invention is not limited by or tothe precise data, methodologies, arrangements and instrumentalitiesshown, but rather only by the claims.

FIG. 1 is a schematic view of a nerve or tissue modulating deviceaccording to the present invention, which supplies controlled pulses ofelectrical current to a magnetic stimulator coil that is continuously incontact with a volume filled with electrically conducting material.

FIG. 2 illustrates an exemplary electrical voltage/current profile for ablocking and/or modulating impulses that are applied to a portion orportions of a nerve, in accordance with an embodiment of the presentdisclsoure.

FIGS. 3A and 3B illustrate top and bottom views respectively of atoroidal magnetic stimulatorin an embodiment of the present invention.

FIGS. 3C and 3D illustrate top and bottom views respectively of atoroidal magnetic stimulator of an embodiment after sectioning along itslong axis to reveal the inside of the stimulator in an embodiment.

FIGS. 4A-4F illustrate different embodiments showing the geometry of thetoroidal core materials around which coils of wire may be wound in anembodiment of the present disclosure.

FIG. 5 illustrates the housing and cap of the dual-toroid magneticstimulator coils of FIG. 3, attached via cable to a box containing thedevice's impulse generator, control unit, and power source.

FIG. 6 illustrates the approximate position of the housing of themagnetic stimulator coil according one embodiment of the presentdisclosure, when the coil is used to stimulate the vagus nerve in theneck of a patient.

FIG. 7 illustrates the housing of the magnetic stimulator coil accordingone embodiment of the present invention, as the coil is positioned tostimulate the vagus nerve in a patient's neck via electricallyconducting gel (or some other conducting material), which is applied tothe surface of the neck in the vicinity of the identified anatomicalstructures.

FIG. 8 illustrates mechanisms or pathways through which stimulation ofthe vagus nerve may reduce inflammation in patients withneurodegenerative disorders.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the present invention, energy is transmitted non-invasively to apatient. In one of the preferred embodiments, a time-varying magneticfield originating outside of a patient is generated, such that themagnetic field induces an electromagnetic field and/or eddy currentswithin tissue of the patient. The invention is particularly useful forinducing applied electrical impulses that interact with the signals ofone or more nerves, or muscles, to achieve a therapeutic result. Inparticular, the present disclosure describes devices and methods totreat neurodegenerative diseases, including Alzheimer's disease,Parkinson's disease, multiple sclerosis, postoperative cognitivedysfunction, and postoperative delirium.

In an exemplary embodiment, the present invention includes methods anddevices for inducing, by a time-varying magnetic field, electricalfields and current within tissue, in accordance with Faraday's law ofinduction. Magnetic stimulation is non-invasive because the magneticfield is produced by passing a time-varying current through a coilpositioned outside the body, inducing at a distance an electric fieldand electric current within electrically-conducting bodily tissue.Because the induced electric field and induced current depend not onlyupon current being passed through wire of the coil, but also upon thepermeability of core material around which the coil may be wound, theterm coil as used herein refers not only to the current-carrying wire,but also to the core material, unless otherwise indicated. Large, pulsedmagnetic fields (PMF) can induce significant electric fields inconducting media, including human tissue. Particular waveforms andamplitudes can stimulate action potentials in nerves, both in vitro andin vivo. Due to the noninvasive nature of the stimulation, PMF deviceshave found utility in several clinical applications, boththerapeutically, e.g., for treating depression via transcranial magneticstimulation (TMS), and diagnostically, for peripheral nerve stimulation.It is an objective of the present invention to use magnetic stimulationto produce significantly less pain or discomfort, as compared with thatexperienced by the patient undergoing a treatment with TENS, for a givendepth of stimulus penetration. Or conversely, for a given amount of painor discomfort on the part of the patient (e.g., the threshold at whichsuch discomfort or pain begins), an objective of the present inventionis to achieve a greater depth of penetration of the stimulus under theskin.

The principle of operation of magnetic stimulation, along with adescription of commercially available equipment and a list of medicalapplications of magnetic stimulation, is reviewed in: Chris HOVEY andReza Jalinous, The Guide to Magnetic Stimulation, The Magstim CompanyLtd, Spring Gardens, Whitland, Carmarthenshire, SA34 OHR, UnitedKingdom, 2006. The types of the magnetic stimulator coils that aredescribed there include circular, parabolic, figure-of-eight(butterfly), and custom designs. Additional types of the magneticstimulator coils are described in U.S. Pat. No. 6,179,770, entitled Coilassemblies for magnetic stimulators, to MOULD; as well as in Kent DAVEY.Magnetic Stimulation Coil and Circuit Design. IEEE Transactions onBiomedical Engineering, Vol. 47 (No. 11, November 2000): 1493-1499 andin HSU KH, Nagarajan S S, Durand D M. Analysis of efficiency of magneticstimulation. IEEE Trans Biomed Eng. 2003 November; 50 (11):1276-85.

The circuits that are used to send pulses or other waveforms throughmagnetic stimulator coils are also described by HOVEY and Jalinous inThe Guide to Magnetic Stimulation that was cited above. Custom magneticstimulator circuits for control, impulse generator and power supply havealso been described [Eric BASHAM, Zhi Yang, Natalia Tchemodanov, andWentai Liu. Magnetic Stimulation of Neural Tissue Techniques and SystemDesign. pp. 293-352, In: Implantable Neural Prostheses 1, Devices andApplications, D. Zhou and E. Greenbaum, eds., New York: Springer (2009);U.S. Pat. No. 7,744,523, entitled Drive circuit for magneticstimulation, to EPSTEIN; U.S. Pat. No. 5,718,662, entitled Apparatus forthe magnetic stimulation of cells or tissue, to JANILOUS;U.S. Pat. No.5,766,124, entitled Magnetic stimulator for neuro-muscular tissue, toPOLSON].

As described in the above-cited publications, the circuits for magneticstimulators are generally complex and expensive. They use a high currentimpulse generator that may produce discharge currents of 5,000 amps ormore, which is passed through the stimulator coil, and which therebyproduces a magnetic pulse. Typically, a transformer charges a capacitorin the impulse generator, which also contains circuit elements thatlimit the effect of undesirable electrical transients. Charging of thecapacitor is under the control of a control unit, which acceptsinformation such as the capacitor voltage, power and other parametersset by the user, as well as from various safety interlocks within theequipment that ensure proper operation, and the capacitor is thendischarged through the coil via an electronic switch (e.g., a controlledrectifier) when the user wishes to apply the stimulus. Greaterflexibility is obtained by adding to the impulse generator a bank ofcapacitors that can be discharged at different times. Thus, higherimpulse rates may be achieved by discharging capacitors in the banksequentially, such that recharging of capacitors is performed whileother capacitors in the bank are being discharged. Furthermore, bydischarging some capacitors while the discharge of other capacitors isin progress, by discharging the capacitors through resistors havingvariable resistance, and by controlling the polarity of the discharge,the control unit may synthesize pulse shapes that approximate anarbitrary function.

In the preferred embodiments of the present invention, the disclosedmethods use a magnetic stimulation device that requires significantlyless electrical current to be passed through its coil(s) than magneticstimulation devices currently known in the art. That low-currentmagnetic stimulation device also has control circuits, impulsegenerators, and power supplies that are significantly less complex thanmagnetic stimulation devices currently known in the art. In fact, themagnetic stimulation device used in preferred embodiments of the presentinvention requires so little power that it can be operated usingconventional low-voltage batteries, thereby reducing the cost tomanufacture the device and allowing for portability of the device. Thelow-current magnetic stimulation device was disclosed in Applicant'sco-pending U.S. patent application Ser. No. 12/964,050 entitled MagneticStimulation Devices and Methods of Therapy, to SIMON et al, which ishereby incorporated by reference in its entirety for all purposes.

A practical disadvantage of conventional magnetic stimulator coils isthat they overheat when used over an extended period of time, becauselarge coil currents are required to reach threshold electric fields inthe stimulated tissue. At high repetition rates, currents can heat thecoils to unacceptable levels in seconds to minutes, depending on thepower levels and pulse durations and rates. Accordingly, coil-coolingequipment is used, which adds complexity to the magnetic stimulatorcoils. Two approaches to overcome heating are to cool the coils withflowing water or air or to increase the magnetic fields using ferritecores (thus allowing smaller currents). For some applications whererelatively long treatment times at high stimulation frequencies may berequired, e.g. treating asthma by stimulating the vagus nerve, neitherof these two approaches may be adequate. Water-cooled coils overheat ina few minutes. Ferrite core coils heat more slowly due to the lowercurrents and heat capacity of the ferrite core, but they also coolslowly and do not allow for water-cooling because the ferrite coreoccupies the volume where the cooling water would flow. One solution tothis problem is to use a core that contains ferrofluids [U.S. Pat. No.7,396,326 and published applications US20080114199, US20080177128, andUS20080224808, all entitled Ferrofluid cooling and acoustical noisereduction in magnetic stimulators, respectively to GHIRON et al., RIEHLet al., RIEHL et al. and GHIRON et al.]. However, even the use offerrofluids may be inadequate when long treatment times at highstimulation frequencies may be required.

In preferred embodiments of the present invention, applicant'sabove-mentioned low-current magnetic stimulation device is used, whichrequires so little electrical current to be passed through its coil(s)that no special cooling apparatus is required to operate the device.That device may therefore be operated at high repetition rates for anindefinite period of time. In other embodiments or the presentinvention, higher current magnetic stimulation coils are used, which maybe cooled using methods and devices that Applicant disclosed inco-pending U.S. patent application Ser. No. 12/859,568 entitledNon-invasive Treatment of Bronchial Constriction, to SIMON, which ishereby incorporated by reference in its entirety for all purposes. Thatapplication also disclosed methods and devices for the stimulation ofnerves other than magnetic stimulation devices and methods, includingmechanical and/or acoustical, optical and/or thermal, andelectrode-based electrical methods and devices, each of which may beused in alternate embodiments of the present invention in lieu of, or inaddition to, the preferred magnetic stimulation devices and methods.

Another problem that is sometimes encountered during magneticstimulation is the unpleasantness or pain that is experienced by thepatient in the vicinity of the stimulated tissue. Little is known aboutthe mechanism that produces the pain, although it is generallyrecognized that magnetic stimulation produces less pain than itselectrode-based counterpart. Most investigations that address thisquestion examine pain associated with transcranial stimulation.

ANDERSON et al found that when magnetic stimulation is repeated over thecourse of multiple sessions, the patients adapt to the pain and exhibitprogressively less discomfort [Berry S. ANDERSON, Katie Kavanagh,Jeffrey J. Borckardt, Ziad H. Nahas, Samet Kose, Sarah H. Lisanby,William M. McDonald, David Avery, Harold A. Sackeim, and Mark S. George.Decreasing Procedural Pain Over Time of Left Prefrontal rTMSforDepression: Initial Results from the Open-Label Phase of a MultisiteTrial (OPT-TMS). Brain Stimul. 2009 Apr. 1; 2(2): 88-92]. Other thanwaiting for the patient to adapt, strategies to reduce the pain include:use of anesthetics placed on or injected into the skin near thestimulation and placement of foam pads on the skin at the site ofstimulation [Jeffrey J. BORCKARDT, Arthur R. Smith, Kelby Hutcheson,Kevin Johnson, Ziad Nahas, Berry Anderson, M. Bret Schneider, Scott T.Reeves, and Mark S. George. Reducing Pain and Unpleasantness DuringRepetitive Transcranial Magnetic Stimulation. Journal of ECT 2006;22:259-264], use of nerve blockades [V. HAKKINEN, H. Eskola, A.Yli-Hankala, T. Nurmikko and S. Kolehmainen. Which structures aresensitive to painful transcranial stimulation? Electromyogr. clin.Neurophysiol. 1995, 35:377-383], the use of very short stimulationpulses [V. SUIHKO. Modelling the response of scalp sensory receptors totranscranial electrical stimulation. Med. Biol. Eng. Comput., 2002, 40,395-401], and providing patients with the amount of information thatsuits their personalities [Anthony DELITTO, Michael J Strube, Arthur DShulman, Scott D Minor. A Study of Discomfort with ElectricalStimulation. Phys. Ther. 1992; 72:410-424]. U.S. Pat. No. 7,614,996,entitled Reducing discomfort caused by electrical stimulation, to RIEHLdiscloses the application of a secondary stimulus to counteract whatwould otherwise be an uncomfortable primary stimulus.

However, these methods of reducing pain or discomfort on the part of thestimulated patient are not always successful or practical. Accordingly,in the preferred embodiments of the present invention, applicant'sabove-mentioned low-current magnetic stimulation device is used, whichproduces significantly less pain or discomfort (if any) to the patientthan magnetic stimulator devices that are currently known in the art.

To achieve the objectives of the present invention, applicant'sabove-mentioned low-current magnetic stimulation device uses anefficient method to produce electric fields in tissue noninvasively,namely, to use a toroidal winding around a high magnetic permeabilitymaterial core, embedded in a conducting medium [Rafael CARBUNARU andDominique M. Durand. Toroidal coil models for transcutaneous magneticstimulation of nerves. IEEE Transactions on Biomedical Engineering. 48(No. 4, April 2001): 434-441]. The conducting medium must have directcontact with skin for current to flow from the coil into the tissue. Inessence, Applicant's device produces a transcutaneous current, similarto a transcutaneous electrical nerve stimulation (TENS) device, but withgreater depth of penetration and virtually no unpleasant peripheralnerve stimulation. In addition, to generate electric fields equivalentto other PMF devices, toroidal stimulators require only about 0.001-0.1of the current and produce virtually no heating. It is understood thatthe magnetic field of a toroidal magnetic stimulator remains essentiallywithin the toroid, and that when referring to this device as a magneticstimulator, it is in fact the electric fields and/or currents that areinduced outside the stimulator that produce an effect in the patient,not the magnetic field.

To the applicant's knowledge, no significant development oftoroidal-coil magnetic stimulators has taken place beyond what wasreported in the above-mentioned CARBUNARU and Durand publication and thedissertation upon which it was based [Rafael Carbunaru FAIERSTEIN, CoilDesigns for Localized and Efficient Magnetic Stimulation of the NervousSystem. Ph.D. Dissertation, Department of Biomedical Engineering, CaseWestern Reserve, May, 1999. (UMI Microform Number: 9940153, UMI Company,Ann Arbor Mich.)]. Toroidal coils or partial-toroids were mentioned inthe following patents or patent applications, but they did not developthe use of a conducting medium in contact with skin: US20080027513,entitled Systems And Methods For Using A Butterfly Coil To CommunicateWith Or Transfer Power To An Implantable Medical Device, to CARBUNARU;U.S. Pat. No. 7,361,136, entitled Method and apparatus for generating atherapeutic magnetic field, to PARKER; U.S. Pat. No. 6,527,695, entitledMagnetic stimulation coil and circuit design, to DAVEY et al.; U.S. Pat.No. 6,155,966, entitled Apparatus and method for toning tissue with afocused, coherent electromagnetic field, to PARKER; U.S. Pat. No.4,915,110, entitled Therapeutic electrostatic device, to KITOV;US20070032827, entitled Methods and apparatus for producing therapeuticand diagnostic stimulation, to KATIMS; US20100222629, entitled Methodand apparatus for magnetic induction therapy, to BURNETT et al. Thelatter application to BURNETT et al. only notes that “in the papertitled ‘Contactless Nerve Stimulation and Signal Detection by InductiveTransducer’ presented at the 1969 Symposium on Application of Magnetismin Bioengineering, Maass et al. disclosed that a nerve threading thelumen of a toroid could be stimulated by a magnetic field.”

The lack of development is apparently due to the difficulty of embeddingthe coil in a practical conducting medium and having that medium besafely in direct contact with human skin. The only reportedtoroidal-coil magnetic stimulation device used to stimulate human nerveswas described in the above-cited dissertation by Rafael CarbunaruFAIERSTEIN, and it embedded the coil in agar. Agar degrades in time andis not ideal to use against skin, presenting difficulties with cleaningit from a patient and within a device. Furthermore, as disclosed there,the toroid needs to be surrounded by conducting medium above, below andaround it, making for a relatively bulky device that is difficult toapply to target tissue having small cross sectional area. Furthermore,the device that FAIERSTEIN discloses cannot be applied to the surface ofthe skin at an arbitrary orientation.

In preferred embodiments of the present invention, Applicant'slow-current, toroidal-coil magnetic stimulation device is used. Thedevice may be applied to body surfaces having an arbitrary orientationwith respect to the long-axis of the component containing the coil.Additional advantages of embodiments of Applicant's device are that theembodiments are compact and portable, and that they may be adapted foruse in nerve and tissue stimulation applications that treat diversemedical conditions. Applicant's co-pending patent application that wasmentioned above Ser. No. 12/964,050 entitled Magnetic StimulationDevices and Methods of Therapy, disclosed methods for using the deviceto treat such conditions as post-operative ileus, dysfunction associatedwith TNF-alpha in Alzheimer's disease, postoperative cognitivedysfunction, rheumatoid arthritis, bronchoconstriction, urinaryincontinence and/or overactive bladder, and sphincter of Oddidysfunction. The present application extends disclosure of the range ofconditions that may be treated by magnetic stimulation or othernon-invasive techniques, by disclosing methods and devices for treatingneurodegenerative diseases more generally.

The present invention discloses methods for using vagal nervestimulation to suppress neuroinflammation. In certain embodiments,methods and devices of the present invention involve the inhibition ofpro-inflammatory cytokines, or more specifically, stimulation of thevagus nerve to inhibit and/or block the release of such pro-inflammatorycytokines. In other embodiments, the present invention discloses use ofvagal nerve stimulation to increase the concentration or effectivenessof anti-inflammatory cytokines. TRACEY et al do not consider themodulation of anti-inflammatory cytokines to be part of the cholinergicanti-inflammatory pathway that their method of vagal nerve stimulationis intended to activate. Thus, they explain that “activation of vagusnerve cholinergic signaling inhibits TNF (tumor necrosis factor) andother proinflammatory cytokine overproduction through ‘immune’ a7nicotinic receptor-mediated mechanisms” [V. A. PAVLOV and K. J. Tracey.Controlling inflammation: the cholinergic anti-inflammatory pathway.Biochemical Society Transactions 34, (2006, 6): 1037-1040]. In contrast,anti-inflammatory cytokines are said to be part of a different“diffusible anti-inflammatory network, which includes glucocorticoids,anti-inflammatory cytokines, and other humoral mediators” [CZURA 0,Tracey K J. Autonomic neural regulation of immunity. J Intern Med.257(2005, 2): 156-66]. Others make a similar distinction between vagaland humoral mediation [GUYON A, Massa F, Rovère C, Nahon J L. Howcytokines can influence the brain: a role for chemokines?J Neuroimmunol2008; 198:46-55].

The disclaiming by TRACEY and colleagues of a role for anti-inflammatorycytokines as mediators of inflammation following stimulation of thevagus nerve may be due to a recognition that anti-inflammatory cytokines(e.g., TGF-β) are usually produced constitutively, whilepro-inflammatory cytokines (e.g., TNF-alpha) are not producedconstitutively, but are instead induced. However, anti-inflammatorycytokines are inducible as well as constitutive, so that for example, anincrease in the concentrations of potentially anti-inflammatorycytokines such as transforming growth factor-beta (TGF-β) can in fact beaccomplished through stimulation of the vagus nerve [RA BAUMGARTNER, VADeramo and MA Beaven. Constitutive and inducible mechanisms forsynthesis and release of cytokines in immune cell lines. The Journal ofImmunology 157 (1996, 9): 4087-4093; CORCORAN, Ciaran; Connor, Thomas J;O'Keane, Veronica; Garland, Malcolm R. The effects of vagus nervestimulation on pro- and anti-inflammatory cytokines in humans: apreliminary report. Neuroimmunomodulation 12 (5, 2005): 307-309].

An example of a pro-anti-inflammatory mechanism that is particularlyrelevant to the treatment of multiple sclerosis is as follows. TGF-βconverts undifferentiated T cells into regulatory T (Treg) cells thatblock the autoimmunity that causes demyelination in multiple sclerosis.However, in the presence of interleukin-6, TGF-β also causes thedifferentiation of T lymphocytes into proinflammatory IL-17cytokine-producing T helper 17 (TH17) cells, which promote autoimmunityand inflammation. Thus, it is conceivable that an increase of TGF-βlevels might actually cause or exacerbate inflammation, rather thansuppress it. Accordingly, a step in an embodiment of the methods thatare disclosed herein is to deter TGF-β from realizing itspro-inflammatory potential, by selecting nerve stimulation parametersthat bias the potential of TGF-β towards anti-inflammation, and/or bytreating the patient with an agent such as the vitamin A metaboliteretinoic acid that is known to promote such an anti-inflammatory bias[MUCIDA D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, CheroutreH. Reciprocal TH17 and regulatory T cell differentiation mediated byretinoic acid. Science 317(2007, 5835): 256-60; Sheng XIAO, Hulin Jin,Thomas Korn, Sue M. Liu, Mohamed Oukka, Bing Lim, and Vijay K. Kuchroo.Retinoic acid increases Foxp3+ regulatory T cells and inhibitsdevelopment of Th17 cells by enhancing TGF-β-driven Smad3 signaling andinhibiting IL-6 and IL-23 receptor expression. J Immunol. 181(2008, 4):2277-2284]. Retinoic acid is a member of a class of compounds known asretinoids, comprising three generations: (1) retinol, retinal, retinoicacid (tretinoin, Retin-A), isotretinoin and alitretinoin; (2) etretinateand acitretin; (3) tazarotene, bexarotene and Adapalene.

In one embodiment of the invention, endogenous retinoic acid that isreleased by neurons themselves is used to produce the anti-inflammatorybias. Thus, it is known that vagal nerve stimulation may inducedifferentiation through release of retinoic acid that is produced inneurons from retinaldehyde by retinaldehyde dehydrogenases, and thedisclosed invention promotes anti-inflammatory regulatory T cell (Treg)differentiation by this type of mechanism [van de PAVERT S A, Olivier BJ, Goverse G, Vondenhoff M F, Greuter M, Beke P, Kusser K, Höpken U E,Lipp M, Niederreither K, Blomhoff R, Sitnik K, Agace W W, Randall T D,de Jonge W J, Mebius R E. Chemokine CXCL13 is essential for lymph nodeinitiation and is induced by retinoic acid and neuronal stimulation. NatImmunol. 10(11, 2009): 1193-1199].

The retinoic acid so released might also directly inhibit the release orfunctioning of proinflammatory cytokines, which would be ananti-pro-inflammatory mechanism that is distinct from the one proposedby TRACEY and colleagues [Malcolm Maden. Retinoic acid in thedevelopment, regeneration and maintenance of the nervous system. NatureReviews Neuroscience 8 (2007), 755-765]. However, if the proinflammatorycytokine that is blocked is TNF-alpha, its inhibition in multiplesclerosis patients might be counterproductive. This is because blockingTNF-alpha with the drug lenercept promotes and exacerbates multiplesclerosis attacks rather than delaying them, which might be attributableto the fact that TNF-alpha promotes remyelination and the proliferationof oligodendrocytes that perform the myelination. [ANONYMOUS. TNFneutralization in MS: Results of a randomized, placebo controlledmulticenter study. Neurology 1999, 53:457; ARNETT HA, Mason J, Marino M,Suzuki K, Matsushima G K, Ting J P. TNF alpha promotes proliferation ofoligodendrocyte progenitors and remyelination. Nat Neurosci 2001,4:1116-1122].

In this example, the competence of anti-inflammatory cytokines may bemodulated by the retinoic acid (RA) signaling system of the nervoussystem. The most important mechanism of RA activity is the regulation ofgene expression. This is accomplished by its binding to nuclear retinoidreceptors that are ligand-activated transcription factors. Thus, RA actsas a transcriptional activator for a large number of other, downstreamregulatory molecules, including enzymes, transcription factors,cytokines, and cytokine receptors. Retinoic acid is an essentialmorphogen in vertebrate development and participates in tissueregeneration in the adult [Jorg MEY and Peter MdCaffery. Retinoic AcidSignaling in the Nervous System of Adult Vertebrates. The Neuroscientist10(5, 2004): 409-421]. RA also increases synaptic strength in ahomeostatic response (synaptic scaling) to neuronal inactivity through amechanism involving protein synthesis that requires the participation ofTNF-alpha. RA is also intimately involved in the control of the rhythmicelectrical activity of the brain. More generally, all-trans retinoicacid, 9-cis retinoic acid, and 13-cis retinoic acid are some of a verysmall number of entrainment factors that regulate the naturalrhythmicity of metabolic processes in many types of individual cells[Mehdi Tafti, Norbert B. Ghyselinck. Functional Implication of theVitamin A Signaling Pathway in the Brain. Arch Neurol. 64(12, 2007):1706-1711].

As examples involving other neurodegenerative diseases, stimulation ofnerves to enhance mechanisms involving retinoic acid or its receptorsalso promotes the rescue of dopamine producing cells in Parkinson'sdisease [Stina Friling, Maria Bergsland and Susanna Kjellander.Activation of Retinoid X Receptor increases dopamine cell survival inmodels for Parkinson's disease. BMC Neuroscience 2009, 10:146].Similarly, stimulation of nerves to release retinoic acid or activateits receptors may also promote the clearance of beta amyloids inAlzheimer's disease [Camacho I. E., Serneels L., Spittaels K., MerchiersP., Dominguez D. and De Strooper B. Peroxisome-proliferator-activatedreceptor gamma induces a clearance mechanism for the amyloid-betapeptide. J. Neurosci. 24 (2004), 10908-10917].

The potentially anti-inflammatory cytokine TGF-beta is a member of theTGF-beta superfamily of neurotrophic factors. Neurotrophic factors serveas growth factors for the development, maintenance, repair, and survivalof specific neuronal populations, acting via retrograde signaling fromtarget neurons by paracrine and autocrine mechanisms. Other neurotrophicfactors also promote the survival of neurons during neurodegeneration.These include members of the nerve growth factor (NGF) superfamily, theglial-cell-line-derived neurotrophic factor (GDNF) family, the neurokinesuperfamily, and non-neuronal growth factors such as the insulin-likegrowth factors (IGF) family. However, major problems in using suchneurotrophic factors for therapy are their inability to cross theblood-brain-barrier, adverse effects resulting from binding to thereceptor in other organs of the body and their low diffusion rate[Yossef S. Levy, Yossi Gilgun-Sherki, Eldad Melamed and Daniel Offen.Therapeutic Potential of Neurotrophic Factors in NeurodegenerativeDiseases. Biodrugs 2005; 19 (2): 97-127].

It is known that vagal nerve stimulation and transcranial magneticstimulation can increase the levels of at least one neurotrophic factorin the brain, namely, brain-derived neurotrophic factor (BDNF) in theNGF superfamily, which has been studied extensively in connection withthe treatment of depression. However, vagal nerve stimulation toincrease levels of neurotrophic factors has not been reported inconnection with neurodegenerative diseases. Because BDNF may bemodulated by stimulating the vagus nerve, vagal nerve stimulation maylikewise promote the expression of other neurotrophic factors inpatients with neurodegenerative disease, thereby circumventing theproblem of blood-brain barrier blockage [Follesa P, Biggio F, Gorini G,Caria S, Talani G, Dazzi L, Puligheddu M, Marrosu F, Biggio G. Vagusnerve stimulation increases norepinephrine concentration and the geneexpression of BDNF and bFGF in the rat brain. Brain Research 1179(2007): 28-34; Biggio F, Gorini G, Utzeri C, Olla P, Marrosu F,Mocchetti I, Follesa P. Chronic vagus nerve stimulation induces neuronalplasticity in the rat hippocampus. Int J. Neuropsychopharmacol. 12(9,2009):1209-21; Roberta Zanardini, Anna Gazzoli, Mariacarla Ventriglia,Jorge Perez, Stefano Bignotti, Paolo Maria Rossini, Massimo Gennarelli,Luisella Bocchio-Chiavetto. Effect of repetitive transcranial magneticstimulation on serum brain derived neurotrophic factor in drug resistantdepressed patients. Journal of Affective Disorders 91 (2006) 83-86].Patent application US20100280562, entitled Biomarkers for monitoringtreatment of neuropsychiatric diseases, to PI et al, disclosed themeasurement of GDNF and other neurotrophic factors following vagal nervestimulation. However, that application is concerned with the search forbiomarkers involving the levels of GDNF, rather than a method fortreating a neurodegenerative disease using vagal nerve stimulation.

FIG. 1 is a schematic diagram of a nerve stimulating/modulating device300 for delivering impulses of energy to nerves for the treatment ofmedical conditions. As shown, device 300 may include an impulsegenerator 310; a power source 320 coupled to the impulse generator 310;a control unit 330 in communication with the impulse generator 310 andcoupled to the power source 320; and a magnetic stimulator coil 340coupled via wires to impulse generator coil 310. The stimulator coil 340is toroidal in shape, due to its winding around a toroid of corematerial.

Although the magnetic stimulator coil 340 is shown in FIG. 1 to be asingle coil, in practice the coil may also comprise two or more distinctcoils, each of which is connected in series or in parallel to theimpulse generator 310. Thus, the coil 340 shown in FIG. 1 represents allthe magnetic stimulator coils of the device collectively. In thepreferred embodiment that is disclosed below, coil 340 actually containstwo coils that may be connected either in series or in parallel to theimpulse generator 310.

The item labeled in FIG. 1 as 350 is a volume, surrounding the coil 340,that is filled with electrically conducting medium. As shown, the mediumnot only encloses the magnetic stimulator coil, but is also deformablesuch that it is form-fitting when applied to the surface of the body.Thus, the sinuousness or curvature shown at the outer surface of theelectrically conducting medium 350 correspond also to sinuousness orcurvature on the surface of the body, against which the conductingmedium 350 is applied, so as to make the medium and body surfacecontiguous. As described below in connection with a preferredembodiment, the volume 350 is electrically connected to the patient at atarget skin surface in order to significantly reduce the current passedthrough the coil 340 that is needed to accomplish stimulation of thepatient's nerve or tissue. As also described below in connection with apreferred embodiment, conducting medium in which the coil 340 isembedded need not completely surround the toroid.

The control unit 330 controls the impulse generator 310 to generate asignal for each of the device's magnetic stimulation coils. The signalsare selected to be suitable for amelioration of a particular medicalcondition, when the signals are applied non-invasively to a target nerveor tissue via the magnetic stimulator coil 340. It is noted that nervestimulating/modulating device 300 may be referred to by its function asa pulse generator. Patent application publications US2005/0075701 andUS2005/0075702, both to SHAFER, both of which are incorporated herein byreference, relating to stimulation of neurons of the sympathetic nervoussystem to attenuate an immune response, contain descriptions of pulsegenerators that may be applicable to the present invention, when adaptedfor use with a magnetic stimulator coil. By way of example, a pulsegenerator 300 is also commercially available, such as Agilent 33522AFunction/Arbitrary Waveform Generator, Agilent Technologies, Inc., 5301Stevens Creek Blvd Santa Clara Calif. 95051.

The control unit 330 may also comprise a general purpose computer,comprising one or more CPU, computer memories for the storage ofexecutable computer programs (including the system's operating system)and the storage and retrieval of data, disk storage devices,communication devices (such as serial and USB ports) for acceptingexternal signals from the system's keyboard and computer mouse as wellas any externally supplied physiological signals, analog-to-digitalconverters for digitizing externally supplied analog signals,communication devices for the transmission and receipt of data to andfrom external devices such as printers and modems that comprise part ofthe system, hardware for generating the display of information onmonitors that comprise part of the system, and busses to interconnectthe above-mentioned components. Thus, the user may operate the system bytyping instructions for the control unit 330 at a device such as akeyboard and view the results on a device such as the system's computermonitor, or direct the results to a printer, modem, and/or storage disk.Control of the system may be based upon feedback measured fromexternally supplied physiological or environmental signals.

Parameters for the nerve or tissue stimulation include power level,frequency and train duration (or pulse number). The stimulationcharacteristics of each pulse, such as depth of penetration, strengthand accuracy, depend on the rise time, peak electrical energytransferred to the coil and the spatial distribution of the electricfield. The rise time and peak coil energy are governed by the electricalcharacteristics of the magnetic stimulator and stimulating coil, whereasthe spatial distribution of the induced electric field depends on thecoil geometry and the anatomy of the region of induced current flow. Inone embodiment of the invention, pulse parameters are set in such as wayas to account for the detailed anatomy surrounding the nerve that isbeing stimulated [Bartosz SAWICKI, Robert Szmurto, Przemystaw Ptonecki,Jacek Starzyński, Stanistaw Wincenciak, Andrzej Rysz. MathematicalModelling of Vagus Nerve Stimulation. pp. 92-97 in: Krawczyk, A.Electromagnetic Field, Health and Environment: Proceedings of EHE '07.Amsterdam, 105 Press, 2008]. A single pulse may be monophasic (nocurrent reversal within the coil), biphasic or polyphasic. For rapidrate stimulators, biphasic systems may be used wherein energy isrecovered from each pulse in order to help energize the next.Embodiments of the invention include those that are fixed frequency,where each pulse in a train has the same inter-stimulus interval, andthose that have modulated frequency, where the intervals between eachpulse in a train can be varied.

FIG. 2 illustrates an exemplary electrical voltage/current profile for astimulating, blocking and/or modulating impulse applied to a portion orportions of selected nerves in accordance with an embodiment of thepresent invention. For the preferred embodiment, the voltage and currentrefer to those that are non-invasively induced within the patient by themagnetic stimulator. As shown, a suitable electrical voltage/currentprofile 400 for the blocking and/or modulating impulse 410 to theportion or portions of a nerve may be achieved using pulse generator310. In a preferred embodiment, the pulse generator 310 may beimplemented using a power source 320 and a control unit 330 having, forinstance, a processor, a clock, a memory, etc., to produce a pulse train420 to the stimulator coils(s) 340 that deliver the stimulating,blocking and/or modulating impulse 410 to the nerve. Nervestimulating/modulating device 300 may be externally powered and/orrecharged may have its own power source 320.

The parameters of the modulation signal 400 are preferably programmable,such as the frequency, amplitude, duty cycle, pulse width, pulse shape,etc. An external communication device may modify the pulse generatorprogramming to improve treatment.

In addition, or as an alternative to the devices to implement themodulation unit for producing the electrical voltage/current profile ofthe stimulating, blocking and/or modulating impulse to the magneticstimulator coil, the device disclosed in patent publication No.US2005/0216062 (the entire disclosure of which is incorporated herein byreference) may be employed. U.S. Patent Publication No.: 2005/0216062discloses a multifunctional electrical stimulation (ES) system adaptedto yield output signals for effecting electromagnetic or other forms ofelectrical stimulation for a broad spectrum of different biological andbiomedical applications, including magnetic stimulators, which produce ahigh intensity magnetic field pulse in order to non-invasively stimulatenerves. The system includes an ES signal stage having a selector coupledto a plurality of different signal generators, each producing a signalhaving a distinct shape, such as a sine wave, a square or a saw-toothwave, or simple or complex pulse, the parameters of which are adjustablein regard to amplitude, duration, repetition rate and other variables.Examples of the signals that may be generated by such a system aredescribed in a publication by LIBOFF [A. R. LIBOFF. Signal shapes inelectromagnetic therapies: a primer. pp. 17-37 in: BioelectromagneticMedicine (Paul J. Rosch and Marko S. Markov, eds.). New York: MarcelDekker (2004)]. The signal from the selected generator in the ES stageis fed to at least one output stage where it is processed to produce ahigh or low voltage or current output of a desired polarity whereby theoutput stage is capable of yielding an electrical stimulation signalappropriate for its intended application. Also included in the system isa measuring stage which measures and displays the electrical stimulationsignal operating on the substance being treated as well as the outputsof various sensors which sense conditions prevailing in this substancewhereby the user of the system can manually adjust it or have itautomatically adjusted by feedback to provide an electrical stimulationsignal of whatever type he wishes and the user can then observe theeffect of this signal on a substance being treated.

The stimulating, blocking and/or modulating impulse signal 410preferably has a frequency, an amplitude, a duty cycle, a pulse width, apulse shape, etc. selected to influence the therapeutic result, namely,stimulating, blocking and/or modulating some or all of the transmissionof the selected nerve. For example, the frequency may be about 1 Hz orgreater, such as between about 15 Hz to 50 Hz, more preferably around 25Hz. The modulation signal may have a pulse width selected to influencethe therapeutic result, such as about 20 microseconds or greater, suchas about 20 microseconds to about 1000 microseconds. For example, theelectric field induced by the device within tissue in the vicinity of anerve is 10 to 600 V/m, preferably around 300 V/m. The gradient of theelectric field may be greater than 2 V/m/mm. More generally, thestimulation device produces an electric field in the vicinity of thenerve that is sufficient to cause the nerve to depolarize and reach athreshold for action potential propagation, which is approximately 8 V/mat 1000 Hz.

The preferred embodiment of magnetic stimulator coil 340 comprises atoroidal winding around a core consisting of high-permeability material(e.g., Supermendur), embedded in an electrically conducting medium.Toroidal coils with high permeability cores have been theoreticallyshown to greatly reduce the currents required for transcranial (TMS) andother forms of magnetic stimulation, but only if the toroids areembedded in a conducting medium and placed against tissue with no airinterface. [Rafael CARBUNARU and Dominique M. Durand. Toroidal coilmodels for transcutaneous magnetic stimulation of nerves. IEEETransactions on Biomedical Engineering 48 (No. 4, April 2001): 434-441;Rafael Carbunaru FAIERSTEIN, Coil Designs for Localized and EfficientMagnetic Stimulation of the Nervous System. Ph.D. Dissertation,Department of Biomedical Engineering, Case Western Reserve, May, 1999,page 117 (UMI Microform Number: 9940153, UMI Company, Ann Arbor Mich.)].

In order to explain some of the novelty of the presently disclosedinvention as compared with the device described in the above-mentionedCarbunaru and Durand publication, as well as in the FAIERSTEINdissertation upon which the publication was based, it is useful to firstsummarize the relevant physics of electric fields and currents that areinduced by time-varying magnetic fields, as produced by current-carryingcoils [Richard P. FEYNMAN, Robert B. Leighton, and Matthew Sands. TheFeynman Lectures on Physics. Volume II. Addison-Wesley Publ. Co.(Reading M A, 1964), page 15-15; K. P. ESSELLE and M. A. Stuchly, Neuralstimulation with magnetic fields: Analysis of induced electric fields,IEEE Trans. Biomed. Eng., 39 (July 1992), pp. 693-700; R. BOWTELL and R.M. Bowley. Analytic Calculations of the E-Fields Induced by Time-VaryingMagnetic Fields Generated by Cylindrical Gradient Coils. MagneticResonance in Medicine 44:782-790 (2000); Feng L I U, Huawei Zhao, andStuart Crozier. On the Induced Electric Field Gradients in the HumanBody for Magnetic Stimulation by Gradient Coils in MRI, IEEETransactions on Biomedical Engineering 50: (No. 7, July 2003) pp.804-815].

The magnetic field B may be represented as the curl of a vectorpotential A, where B and A are functions of position and time: B= V×A.

The electric field E, which is also a function of position and time,consists of two parts, E₁ and E₂:E=E₁+E₂. For a current-carrying coil,E₁ is obtained from the vector potential A by:

$E_{1} = {{- \frac{\partial A}{\partial t}} = {- {\int_{\;}^{\;}{\frac{1}{4\pi}\frac{\partial\left( {\mu \; I} \right)}{\partial t}\ \frac{l}{r}}}}}$

where μ is the permeability, I is the current flowing in the coil, dl isan oriented differential element of the coil, r is the distance betweendl and the point at which the electric field E is measured, and theintegral is performed around all the differential elements dl of thecoil.

E₂ is obtained from the gradient of a scalar potential Φ: E₁=−{tildeover (V)}Φ. The scalar potential arises because conductivity changesalong the path of a current, particularly the abrupt change ofconductivity at an air/conductor interface, causes electric charges toseparate and accumulate on the surface of the interface, with theamplitude and sign of the charges changing as a function of surfaceposition. Thus, no conduction current can flow across an air/conductorinterface, so according to the interfacial boundary conditions, thecomponent of any induced current normal to the interface must be zero.The existence of a scalar potential accounts for these effects.

The electrical current density J, which is also a function of positionand time, consists of two parts:J=J₁+J₂, corresponding to the two partsof E: I₂=σE₂ and I₂=σE₂, where the conductivity σ is generally a tensorand a function of position. If the current flows in material that isessentially unpolarizable (i.e., is presumed not to be a dielectric),any displacement current may be ignored, so the current would satisfyAmpere's law:

${\nabla{\times \frac{B}{\mu}}} = {J.}$

Because the divergence of the curl is zero, ∇×J=0. One may substitute J₁and J₂ into that equation to obtain: ∇·(σ

(E

_(J)1−∇Φ))=0. The latter equation has been solved numerically forspecial cases to estimate the currents that are induced by a magneticfield that is inserted into the body [W. WANG, S. R. Eisenberg, Athree-dimensional finite element method for computing magneticallyinduced currents in tissues. IEEE Transactions on Magnetics. 30 (6, Nov.1994): 5015-5023; Bartosz SAWICKI, Robert Szmurto, Przemystaw Ptonecki,Jacek Starzyński, Stanistaw Wincenciak, Andrzej Rysz. MathematicalModelling of Vagus Nerve Stimulation. pp. 92-97 in: Krawczyk, A.Electromagnetic Field, Health and Environment: Proceedings of EHE '07.Amsterdam, IOS Press, 2008]. If the conductivity of material in thedevice (or patient) is itself selected to be a function of the electricfield, then the equation becomes non-linear, which could exhibitmultiple solutions, frequency multiplication, and other such non-linearbehavior.

If the displacement current cannot be ignored, the displacement appearsas a term involving the time-derivative of the electric field in themore general expression: ∇·(ξ(∈E)/ξt+σ

(E

_(t)1−∇Φ))=0, where ∈ is the permittivity, which is a function ofposition and is generally a tensor. As a consequence of such a term, thewaveform of the electric field at any point will generally be alteredrelative to the waveform of the current I(t) that is passed through thecoils. Furthermore, if the permittivity of a material in the device isitself selected to be a function of the electric field, then theequation becomes non-linear, which could exhibit multiple solutions,frequency multiplication, and other such non-linear behavior.

The above-mentioned publication by CARBUNARU and Durand, as well as theFAIERSTEIN dissertation upon which the publication was based, areheretofore unique in that they describe a magnetic stimulation devicethat does not create a magnetic field within the tissues that the deviceis intended to stimulate. Their device instead confines the magneticfield to a toroid, which is the only coil geometry known to create amagnetic field that is completely limited to part of space. With such adevice, the electric field alone penetrates the patient to stimulatenerves or tissue, which they calculate using device-specific equationsfor the fields E₁ and E₂ that were defined above. Unlike conventionalmagnetic stimulation devices, their device's electric field orientationis not limited to fields at the skin that are parallel to the skinsurface, due to the presence of conducting material that extends fromthe skin to (and beyond) the stimulator's coil. The boundary conditionsgiving rise to E₂ were those of an infinite half-space. Thus, theirtoroidal coil was immersed in a homogeneous continuous conductingmaterial that had an air/conductor interface along an infinite planeparallel to the toroid, located at a variable distance from the toroid,and the toroid and conducting material were in contact with a patient'sskin.

In their investigations, Carbunaru and Durand varied E₁ by only changingthe coil geometry (integral over dl) as follows. They investigatedwinding the coil around different core geometries (round, quartercircle, square) and changed the radius and thickness of the core. Theyalso varied E₂ by varying the thickness of the conducting layer in whichthe toroid was immersed, thereby changing boundary conditions only inthat manner. Although Carbunaru and Durand demonstrated that it ispossible to electrically stimulate a patient transcutaneously with sucha device, they made no attempt to develop the device in such a way as togenerally shape the electric field that is to stimulate the nerve. Inparticular, the electric fields that may be produced by their device arelimited to those that are radially symmetric at any given depth ofstimulation into the patient (i.e., z and ρ are used to specify locationof the field, not x, y, and z). This is a significant limitation, and itresults in a deficiency that was noted in FIG. 6 of their publication:“at large depths of stimulation, the threshold current [in the device'scoil] for long axons is larger than the saturation current of the coil.Stimulation of those axons is only possible at low threshold points suchas bending sites or tissue conductivity inhomogeneities”. Thus, fortheir device, varying the parameters that they considered, in order toincrease the electric field or its gradient in the vicinity of a nerve,may come at the expense of limiting the field's physiologicaleffectiveness, such that the spatial extent of the field of stimulationmay be insufficient to modulate the target nerve's function. Yet, suchlong axons are precisely what we may wish to stimulate in therapeuticinterventions, such as the ones disclosed herein. Accordingly, it is anobjective of the present invention to shape an elongated electric fieldof effect that can be oriented parallel to such a long nerve. The term“shape an electric field” as used herein means to create an electricfield or its gradient that is generally not radially symmetric at agiven depth of stimulation in the patient, especially a field that ischaracterized as being elongated or finger-like, and especially also afield in which the magnitude of the field in some direction may exhibitmore than one spatial maximum (i.e. may be bimodal or multimodal) suchthat the tissue between the maxima may contain an area across whichinduced current flow is restricted. Shaping of the electric field refersboth to the circumscribing of regions within which there is asignificant electric field and to configuring the directions of theelectric field within those regions.

Thus, the present invention differs from the device disclosed byCARBUNARU and Durand by deliberately shaping an electric field that isused to transcutaneously stimulate the patient. Our invention does so byconfiguring elements that are present within the equations that weresummarized above, comprising (but not limited to) the followingexemplary configurations that may be used alone or in combination.

First, the contours of the coil differential elements dl that areintegrated in the above equation for E₁ are shaped into a geometry otherthan a single planar toroid. For example, two separate toroidal coilsare used so that E₁ becomes the sum of two integrals, or the shape of asingle toroid is twisted to resemble a figure-of-8 rather than a planartoroid.

Second, the value of the current I in the above equation for E₁ ismanipulated to shape the electric field. For example, if the devicecontains two toroidal coils, the current in one toroid may be thenegative of the current in the other toroid. As another example, themagnitude of the current in a left toroidal coil may be varied relativeto the magnitude of the current in a right toroidal coil, so that thelocation of their superimposed induced electric fields may becorrespondingly moved (focused) in the left or right directions. Asanother example, the waveform of the current in a left toroidal coil maybe different than the waveform of the current in a right toroidal coil,so that their superimposed induced electric fields may exhibit beatfrequencies, as has been attempted with electrode-based stimulators[U.S. Pat. No. 5,512,057, entitled Interferential stimulator forapplying localized stimulation, to REISS et al.], and acousticstimulators [U.S. Pat. No. 5,903,516, entitled Acoustic force generatorfor detection, imaging and information transmission using the beatsignal of multiple intersecting sonic beams, to GREENLEAF et al].

Third, the scalar potential Φ in the above equation for E₂ ismanipulated to shape the electric field. For example, this isaccomplished by changing the boundaries of conductor/air (ornon-conductor) interfaces, thereby creating different boundaryconditions. Whereas the toroid in the CARBUNARU and Durand publicationwas immersed in a homogeneous conducting half-space, this is notnecessarily the case for our invention. Although our invention willgenerally have some continuously conducting path between the device'scoil and the patient's skin, the conducting medium need not totallyimmerse the coil, and there may be insulating voids within theconducting medium. For example, if the device contains two toroids,conducting material may connect each of the toroids individually to thepatient's skin, but there may be an insulating gap (from air or someother insulator) between the surfaces at which conducting materialconnected to the individual toroids contact the patient. Furthermore,the area of the conducting material that contacts the skin may be madevariable, by using an aperture adjusting mechanism such as an irisdiaphragm. As another example, if the coil is wound around core materialthat is laminated, with the core in contact with the device'selectrically conducting material, then the lamination may be extendedinto the conducting material in such a way as to direct the inducedelectrical current between the laminations and towards the surface ofthe patient's skin. As another example, the conducting material may passthrough apertures in an insulated mesh before contacting the patient'sskin, creating thereby an array of electric field maxima.

Fourth, the conductivity σ (in the equations I₁=σE₁ and I₂=σE₂) may bevaried spatially within the device by using two or more differentconducting materials that are in contact with one another, for givenboundary conditions. The conductivity may also be varied by constructingsome conducting material from a semiconductor, which allows foradjustment of the conductivity in space and in time by exposure of thesemiconductor to agents to which they are sensitive, such as electricfields, light at particular wavelengths, temperature, or some otherenvironmental variable over which the user of the device has control.For the special case in which the semiconductor's conductivity may bemade to approach zero, that would approximate the imposition of aninterfacial boundary condition as described in the previous paragraph.As another example, the conducting material of the device may beselected to have a three-dimensional conductivity structure thatapproximates that of the conducting tissue under the patient's skin, butoriented in the opposite and/or mirror image directions, in such a waythat the conductivity is symmetrical on either side of the patient'sskin. Such an arrangement will allow for essentially symmetricalelectrical stimulation of the patient's tissue and the conductingmaterial within the device.

Fifth, a dialectric material having a high permittivity F, such asMylar, neoprene, titanium dioxide, or strontium titanate, may be used inthe device, for example, in order to permit capacitative electricalcoupling to the patient's skin.

Sixth, the present invention is more general than the device describedin the above-mentioned publication of CARBUNARU and Durand in that,although the magnetic field produced by the present invention does noteffectively penetrate the patient's tissue, that feature need not be dueto the use of a toroidal coil. The magnetic field will not effectivelypenetrate the patient's tissue if the field's de minimis existencewithin the patient would produce no significant physiological effect.For example, it would not produce a significant physiological effect ifthe magnitude of the magnetic field were of the same order of magnitudeas the earth's magnetic field. The magnetic field of our discloseddevice may be produced by a coil other than a toroid, wherein themagnetic field outside the coil falls rapidly as a function of distancefrom the coil. For example, the coil may be a solenoid that has anapproximately centrally-confined magnetic field as the density of coilturns and the length of the solenoid increase. As another example, thecoil may be a partial toroid, which would also have a magnetic fieldthat approximates that of a complete toroid as the gap within thepartial-toroid decreases to zero. As another example, even if one isattempting to construct a complete toroidal winding, the presence oflead wires and imperfections of the winding may cause the device inpractice to deviate from the ideal toroid. Such non-toroidal windingsmay be used in the present invention if they are backed away and/ororiented relative to the patient's skin in such a way that the magneticfield that is produced by the device does not effectively penetrate thepatient's tissue. Alternatively, magnetic shielding, such as mumetal,supermalloy, supermumetal, nilomag, sanbold, molybdenum permalloy,Sendust, M-1040, Hipernom and HyMu-80, may be interposed between thepatient and coil of the device in such a way that the magnetic fieldthat is produced by the device does not effectively penetrate thepatient's tissue.

In the dissertation cited above, Carbunaru-FAIERSTEIN made no attempt touse conducting material other than agar in a KCI solution, and he madeno attempt to devise a device that could be conveniently and safelyapplied to a patient's skin, at an arbitrary angle without theconducting material spilling out of its container. It is therefore anobjective of the present invention to disclose conducting material thatcan be used not only to adapt the conductivity σ and select boundaryconditions, thereby shaping the electric fields and currents asdescribed above, but also to create devices that can be appliedpractically to any surface of the body. The volume of the containercontaining electrically conducting medium is labeled in FIG. 1 as 350.Use of the container of conducting medium 350 allows one to generate(induce) electric fields in tissue (and electric field gradients andelectric currents) that are equivalent to those generated using currentmagnetic stimulation devices, but with about 0.001 to 0.1 of the currentconventionally applied to a magnetic stimulation coil. This allows forminimal heating and deeper tissue stimulation. However, application ofthe conducting medium to the surface of the patient is difficult toperform in practice because the tissue contours (head for TMS, arms,legs, neck, etc. for peripheral nerve stimulation) are not planar. Tosolve this problem, in the preferred embodiment of the presentinvention, the toroidal coil is embedded in a structure which is filledwith a conducting medium having approximately the same conductivity asmuscle tissue, as now described.

In one embodiment of the invention, the container contains holes so thatthe conducting material (e.g., a conducting gel) can make physicalcontact with the patient's skin through the holes. For example, theconducting medium 350 may comprise a chamber surrounding the coil,filled with a conductive gel that has the approximate viscosity andmechanical consistency of gel deodorant (e.g., Right Guard Clear Gelfrom Dial Corporation, 15501 N. Dial Boulevard, Scottsdale Ariz. 85260,one composition of which comprises aluminum chlorohydrate, sorbitol,propylene glycol, polydimethylsiloxanes Silicon oil, cyclomethicone,ethanol/SD Alcohol 40, dimethicone copolyol, aluminum zirconiumtetrachlorohydrex gly, and water). The gel, which is less viscous thanconventional electrode gel, is maintained in the chamber with a mesh ofopenings at the end where the device is to contact the patient's skin.The gel does not leak out, and it can be dispensed with a simple screwdriven piston.

In another embodiment, the container itself is made of a conductingelastomer (e.g., dry carbon-filled silicone elastomer), and electricalcontact with the patient is through the elastomer itself, possiblythrough an additional outside coating of conducting material. In someembodiments of the invention, the conducting medium may be a balloonfilled with a conducting gel or conducting powders, or the balloon maybe constructed extensively from deformable conducting elastomers. Theballoon conforms to the skin surface, removing any air, thus allowingfor high impedance matching and conduction of large electric fields into the tissue. A device such as that disclosed in U.S. Pat. No.7,591,776, entitled Magnetic stimulators and stimulating coils, toPHILLIPS et al. may conform the coil itself to the contours of the body,but in the preferred embodiment, such a curved coil is also enclosed bya container that is filled with a conducting medium that deforms to becontiguous with the skin.

Agar can also be used as part of the conducting medium, but it is notpreferred, because agar degrades in time, is not ideal to use againstskin, and presents difficulties with cleaning the patient and stimulatorcoil. Use of agar in a 4M KCI solution as a conducting medium wasmentioned in the above-cited dissertation: Rafael Carbunaru FAIERSTEIN,Coil Designs for Localized and Efficient Magnetic Stimulation of theNervous System. Ph.D. Dissertation, Department of BiomedicalEngineering, Case Western Reserve, May, 1999, page 117 (UMI MicroformNumber: 9940153, UMI Company, Ann Arbor Mich.). However, thatpublication makes no mention or suggestion of placing the agar in aconducting elastomeric balloon, or other deformable container so as toallow the conducting medium to conform to the generally non-planarcontours of a patient's skin having an arbitrary orientation. In fact,that publication describes the coil as being submerged in a containerfilled with an electrically conducting solution. If the coil andcontainer were placed on a body surface that was oriented in thevertical direction, then the conducting solution would spill out, makingit impossible to stimulate the body surface in that orientation. Incontrast, the present invention is able to stimulate body surfaceshaving arbitrary orientation. Examples making use of the present deviceshow the body surface as having many different orientations that areincompatible with the disclosure in the above-cited dissertation.

That dissertation also makes no mention of a dispensing method wherebythe agar would be made contiguous with the patient's skin. A layer ofelectrolytic gel is said to have been applied between the skin and coil,but the configuration was not described clearly in the publication. Inparticular, no mention is made of the electrolytic gel being in contactwith the agar.

Rather than using agar as the conducting medium, the coil can instead beembedded in a conducting solution such as 1-10% NaCl, contacting anelectrically conducting interface to the human tissue. Such an interfaceis used as it allows current to flow from the coil into the tissue andsupports the medium-surrounded toroid so that it can be completelysealed. Thus, the interface is material, interposed between theconducting medium and patient's skin, that allows the conducting medium(e.g., saline solution) to slowly leak through it, allowing current toflow to the skin. Several interfaces are disclosed as follows.

One interface comprises conducting material that is hydrophilic, such asTecophlic from The Lubrizol Corporation, 29400 Lakeland Boulevard,Wickliffe, Ohio 44092. It absorbs from 10-100% of its weight in water,making it highly electrically conductive, while allowing only minimalbulk fluid flow.

Another material that may be used as an interface is a hydrogel, such asthat used on standard EEG, EKG and TENS electrodes [Rylie A GREEN,Sungchul Baek, Laura A Poole-Warren and Penny J. Martens. Conductingpolymer-hydrogels for medical electrode applications. Sci. Technol. Adv.Mater. 11 (2010) 014107 (13 pp)]. For example it may be the followinghypoallergenic, bacteriostatic electrode gel: SIGNAGEL Electrode Gelfrom Parker Laboratories, Inc., 286 Eldridge Rd., Fairfield N.J. 07004.

A third type of interface may be made from a very thin material with ahigh dielectric constant, such as those used to make capacitors. Forexample, Mylar can be made in submicron thicknesses and has a dielectricconstant of about 3. Thus, at stimulation frequencies of severalkilohertz or greater, the Mylar will capacitively couple the signalthrough it because it will have an impedance comparable to that of theskin itself. Thus, it will isolate the toroid and the solution it isembedded in from the tissue, yet allow current to pass.

The preferred embodiment of the magnetic stimulator coil 340 in FIG. 1reduces the volume of conducting material that must surround a toroidalcoil, by using two toroids, side-by-side, and passing electrical currentthrough the two toroidal coils in opposite directions. In thisconfiguration, the induced current will flow from the lumen of onetoroid, through the tissue and back through the lumen of the other,completing the circuit within the toroids' conducting medium. Thus,minimal space for the conducting medium is required around the outsideof the toroids at positions near from the gap between the pair of coils.An additional advantage of using two toroids in this configuration isthat this design will greatly increase the magnitude of the electricfield gradient between them, which is crucial for exciting long,straight axons such as the vagus nerve and certain peripheral nerves.

This preferred embodiment of the invention is shown in FIG. 3. FIGS. 3Aand 3B respectively provide top and bottom views of the outer surface ofthe toroidal magnetic stimulator 30. FIGS. 3C and 3D respectivelyprovide top and bottom views of the toroidal magnetic stimulator 30,after sectioning along its long axis to reveal the inside of thestimulator.

FIGS. 3A-3D all show a mesh 31 with openings that permit a conductinggel to pass from the inside of the stimulator to the surface of thepatient's skin at the location of nerve or tissue stimulation. Thus, themesh with openings 31 is the part of the stimulator that is applied tothe skin of the patient.

FIGS. 3B-3D show openings at the opposite end of the stimulator 30. Oneof the openings is an electronics port 32 through which wires pass fromthe stimulator coil(s) to the impulse generator (310 in FIG. 1). Thesecond opening is a conducting gel port 33 through which conducting gelmay be introduced into the stimulator 30 and through which ascrew-driven piston arm may be introduced to dispense conducting gelthrough the mesh 31. The gel itself will be contained withincylindrical-shaped but interconnected conducting medium chambers 34 thatare shown in FIGS. 3C and 3D. The depth of the conducting mediumchambers 34, which is approximately the height of the long axis of thestimulator, affects the magnitude of the electric fields and currentsthat are induced by the device [Rafael CARBUNARU and Dominique M.Durand. Toroidal coil models for transcutaneous magnetic stimulation ofnerves. IEEE Transactions on Biomedical Engineering. 48 (No. 4, April2001): 434-441].

FIGS. 3C and 3D also show the coils of wire 35 that are wound aroundtoroidal cores 36, consisting of high-permeability material (e.g.,Supermendur). Lead wires (not shown) for the coils 35 pass from thestimulator coil(s) to the impulse generator (310 in FIG. 1) via theelectronics port 32. Different circuit configurations are contemplated.If separate lead wires for each of the coils 35 connect to the impulsegenerator (i.e., parallel connection), and if the pair of coils arewound with the same handedness around the cores, then the design is forcurrent to pass in opposite directions through the two coils. On theother hand, if the coils are wound with opposite handedness around thecores, then the lead wires for the coils may be connected in series tothe impulse generator, or if they are connected to the impulse generatorin parallel, then the design is for current to pass in the samedirection through both coils.

As seen in FIGS. 3C and 3D, the coils 35 and cores 36 around which theyare wound are mounted as close as practical to the corresponding mesh 31with openings through which conducting gel passes to the surface of thepatient's skin. As seen in FIG. 3D, each coil and the core around whichit is wound is mounted in its own housing 37, the function of which isto provide mechanical support to the coil and core, as well as toelectrically insulate a coil from its neighboring coil. With thisdesign, induced current will flow from the lumen of one toroid, throughthe tissue and back through the lumen of the other, completing thecircuit within the toroids' conducting medium.

Different diameter toroidal coils and windings may be preferred fordifferent applications. For a generic application, the outer diameter ofthe core may be typically 1 to 5 cm, with an inner diameter typically0.5 to 0.75 of the outer diameter. The coil's winding around the coremay be typically 3 to 250 in number, depending on the core diameter anddepending on the desired coil inductance.

The embodiment shown in FIG. 3 contains two toroids, in which the outersurface of the toroids are planar, the toroids lie side-by-side, and thecorresponding outer surfaces for both toroids lie essentially in thesame plane. Many different embodiments are also contemplated, each ofwhich may be better suited to the stimulation of particular nerves ortissues. Examples of such alternate embodiments are illustrated in FIG.4, showing the geometry of the toroidal core material around which coilsof wire (not shown) would be wound. The darkened faces of the figuresshown there indicate the faces that would be oriented towards thepatient's skin. Instead of placing the toroids side-by-side as in FIG.3, a pair of toroids may be placed concentrically as shown in FIG. 4A.Instead of using two toroids, any number could be used, as illustratedby FIG. 4B that shows four concentrically positioned toroids. Individualplanar toroids need not all lie in the same plane, as shown in FIG. 4C.In fact, the toroids themselves need not have a planar structure, asillustrated in FIGS. 4D and 4E. Furthermore, the toroids need not have around structure or a structure comprising arcs, as illustrated in FIG.4F, which shows a pair of concentrically positioned square toroids. Theexamples shown here have toroids that are rectangular or square whensectioned perpendicular to their perimeters. In other embodiments, thesectioned toroid could have any other closed geometry, such as a circleor an ellipse or a geometry that changes from one part of the toroid toanother.

Thus, the geometrical configuration of the disclosed device is general.For example, it may comprise a plurality of toroids. It may comprise twotoroids wherein one toroid lies within the aperture of the secondtoroid. A surface having a minimum area that fills an aperture of atoroid need not lie within a plane. The projection of the volume of atoroidal core onto a plane need not produce a circular shape around anyperimeter of any such projection. For a plurality of toroids, a planehaving a greatest area of intersection through one toroid among theplurality may, but need not, be parallel to a plane having a greatestarea of intersection through some second toroid among the plurality.

The design and methods of use of impulse generators, control units, andstimulator coils for magnetic stimulators are informed by the designsand methods of use of impulse generators, control units, and electrodes(with leads) for comparable completely electrical nerve stimulators, butdesign and methods of use of the magnetic stimulators must take intoaccount many special considerations, making it generally notstraightforward to transfer knowledge of completely electricalstimulation methods to magnetic stimulation methods. Such considerationsinclude determining the anatomical location of the stimulation anddetermining the appropriate pulse configuration [OLNEY RK, So Y T,Goodin D S, Aminoff Mt A comparison of magnetic and electric stimulationof peripheral nerves. Muscle Nerve 1990:13:957-963; J. NILSSON, M.Panizza, B. J. Roth et al. Determining the site of stimulation duringmagnetic stimulation of the peripheral nerve, Electroencephalographs andclinical neurophysiology. vol 85, pp. 253-264, 1992; Nafia AL-MUTAWALY,Hubert de Bruin, and Gary Hasey. The Effects of Pulse Configuration onMagnetic Stimulation. Journal of Clinical Neurophysiology 20(5):361-370,2003].

In the preferred embodiment of the invention, electronic components ofthe stimulator (impulse generator, control unit, and power source) arecompact, portable, and simple to operate. The preferred simplicity isillustrated in FIG. 5, which shows the stimulator coil housing 30(illustrated in more detail as 30 in FIG. 3), which is connected byelectrical cable to a circuit control box 38. As shown in FIG. 5, thecircuit control box 38 will generally require only an on/off switch anda power controller, provided that the parameters of stimulationdescribed in connection with FIG. 2 have already been programmed for theparticular application of the device. For such a portable device, poweris provided by batteries, e.g., a 9 volt battery or two to six 1.5V AAbatteries. A covering cap 39 is also provided to fit snugly over themesh (31 in FIG. 3) of the stimulator coil housing 30, in order to keepthe housing's conducting medium from leaking or drying when the deviceis not in use.

In the preferred embodiment for a generic therapeutic application, thecurrents passing through the coils of the magnetic stimulator willsaturate the core (e.g., 0.1 to 2 Tesla magnetic field strength forSupermendur core material). This will require approximately 0.5 to 20amperes of current being passed through each coil, typically 2 amperes,with voltages across each coil of 10 to 100 volts. The current is passedthrough the coils in bursts of pulses. The burst repeats at 1 Hz to 5000Hz, preferably at 15-50 Hz. The pulses have duration of 20 to 1000microseconds, preferably 200 microseconds and there may be 1 to 20pulses per burst. Other waveforms described above in connection withFIG. 2 are also generated, depending on the nerve or tissue stimulationapplication.

Examples in the remaining disclosure will be directed to use of thedisclosed toroidal magnetic stimulation device for treatment of specificmedical conditions. These applications involve stimulating a patient inand around the patient's neck. However, it will be appreciated that thesystems and methods of the present invention can be applied equally wellto other tissues and nerves of the body, including but not limited toparasympathetic nerves, sympathetic nerves, spinal or cranial nerves,and brain tissue. In addition, the present invention can be used todirectly or indirectly stimulate or otherwise modulate nerves thatinnervate smooth or skeletal muscle, endocrine glands, and organs of thedigestive system.

In some preferred embodiments of methods that make use of the disclosedtoroidal-coil magnetic stimulation device, selected nerve fibers arestimulated. These include stimulation of the vagus nerve at a locationin the patient's neck. At that location, the vagus nerve is situatedwithin the carotid sheath, near the carotid artery and the interiorjugular vein. The carotid sheath is located at the lateral boundary ofthe retopharyngeal space on each side of the neck and deep to thesternocleidomastoid muscle. The left vagus nerve is ordinarily selectedfor stimulation because stimulation of the right vagus nerve may produceundesired effects on the heart.

The three major structures within the carotid sheath are the commoncarotid artery, the internal jugular vein and the vagus nerve. Thecarotid artery lies medial to the internal jugular vein, and the vagusnerve is situated posteriorly between the two vessels. Typically, thelocation of the carotid sheath or interior jugular vein in a patient(and therefore the location of the vagus nerve) will be ascertained inany manner known in the art, e.g., by feel or ultrasound imaging.Proceeding from the skin of the neck above the sternocleidomastoidmuscle to the vagus nerve, a line may pass successively through thesternocleidomastoid muscle, the carotid sheath and the internal jugularvein, unless the position on the skin is immediately to either side ofthe external jugular vein. In the latter case, the line may passsuccessively through only the sternocleidomastoid muscle and the carotidsheath before encountering the vagus nerve, missing the interior jugularvein. Accordingly, a point on the neck adjacent to the external jugularvein might be preferred for non-invasive stimulation of the vagus nerve.The magnetic stimulator coil may be centered on such a point, at thelevel of about the fifth to sixth cervical vertebra.

FIG. 6 illustrates use of the device shown in FIG. 3 and FIG. 5 tostimulate the vagus nerve at that location in the neck, in which thestimulator device 30 is applied to the target location on the patient'sneck as described above. For reference, locations of the followingvertebrae are also shown: first cervical vertebra 71, the fifth cervicalvertebra 75, the sixth cervical vertebra 76, and the seventh cervicalvertebra 77.

FIG. 7 provides a more detailed view of use of the toroidal magneticstimulator device, when positioned to stimulate the vagus nerve at theneck location that is indicated in FIG. 6. As shown, the toroidalmagnetic stimulator 30 touches the neck indirectly, by making electricalcontact through conducting gel 29 (or other conducting material) that isdispensed through mesh openings of the stimulator (identified as 31 inFIG. 3). The layer of conducting gel 29 in FIG. 7 is shown to connectthe device to the patient's skin, but it is understood that the actuallocation of the gel layer(s) is generally determined by the location ofmesh 31 shown in FIG. 3A. It is also understood that the device 30 isconnected via wires or cables (not shown) to an impulse generator 310 asin FIG. 1. The vagus nerve 60 is identified in FIG. 7, along with thecarotid sheath 61 that is identified there in bold peripheral outline.The carotid sheath encloses not only the vagus nerve, but also theinternal jugular vein 62 and the common carotid artery 63. Features thatmay be identified near the surface of the neck include the externaljugular vein 64 and the sternocleidomastoid muscle 65. Additional organsin the vicinity of the vagus nerve include the trachea 66, thyroid gland67, esophagus 68, scalenus anterior muscle 69, and scalenus mediusmuscle 70. The sixth cervical vertebra 76 is also shown in FIG. 7, withbony structure indicated by hatching marks.

Magnetic stimulation has been used by several investigators tonon-invasively stimulate the vagus nerve, in the neck and at otherlocations. In a series of articles beginning in 1992, Aziz andcolleagues describe using non-invasive magnetic stimulation toelectrically stimulate the vagus nerve in the neck. [Q. AZIZ et al.Magnetic Stimulation of Efferent Neural Pathways to the HumanOesophagus. Gut 33: S53-S70 (Poster Session F218) (1992); AZIZ, Q., J.C. Rothwell, J. Barlow, A. Hobson, S. Alani, J. Bancewicz, and D. G.Thompson. Esophageal myoelectric responses to magnetic stimulation ofthe human cortex and the extracranial vagus nerve. Am. J. Physiol. 267(Gastrointest. Liver Physiol. 30): G827-G835, 1994; Shaheen HAMDY, QasimAziz, John C. Rothwell, Anthony Hobson, Josephine Barlow, and David G.Thompson. Cranial nerve modulation of human cortical swallowing motorpathways. Am. J. Physiol. 272 (Gastrointest. Liver Physiol. 35):G802-G808, 1997; Shaheen HAMDY, John C. Rothwell, Qasim Aziz, Krishna D.Singh, and David G. Thompson. Long-term reorganization of human motorcortex driven by short-term sensory stimulation. Nature Neuroscience 1(issue 1, May 1998):64-68.] SIMS and colleagues stimulated the vagusnerve at and near the mastoid tip. [H. Steven SIMS, Toshiyuki Yamashita,Karen Rhew, and Christy L. Ludlow. Assessing the clinical utility of themagnetic stimulator for measuring response latencies in the laryngealmuscles. Otolaryngol Head Neck Surg 1996; 114:761-7]. KHEDR andcolleagues also used a magnetic stimulator to stimulate the vagus nerveat the tip of the mastoid bone [E. M. KHEDR and E-E. M. ArefElectrophysiological study of vocal-fold mobility disorders using amagnetic stimulator. European Journal of Neurology 2002, 9: 259-267;KHEDR, E. M., Abo-Elfetoh, N., Ahmed, M. A., Kamel, N. F., Farook, M.,El Karn, M. F. Dysphagia and hemispheric stroke: A transcranial magneticstudy. Neurophysiologie Clinique/Clinical Neurophysiology (2008) 38,235-242)]. SHAFIK stimulated the vagus nerve in the neck, placing themagnetic stimulator on the neck between the sternomastoid muscle and thetrachea. [A. SHAFIK. Functional magnetic stimulation of the vagus nerveenhances colonic transit time in healthy volunteers. Tech Coloproctol(1999) 3:123-12]. Among these investigations, the one by SHAFIKstimulated the vagus nerve for the longest period of time. He stimulatedat 175 joules per pulse, 40 Hz frequency, 10 seconds on, 10 seconds offfor 20 minutes duration and followed by 60 minutes of rest, and thissequence was performed for 5 cycles in each subject.

The vagus is not the only nerve that may be stimulated non-invasively inthe neck using magnetic stimulation. For example, the phrenic nerve hasalso been magnetically stimulated. [SIMILOWSKI, T., B. Fleury, S.Launois, H. P. Cathala, P. Bouche, and J. P. Derenne. Cervical magneticstimulation: a new painless method for bilateral phrenic nervestimulation in conscious humans. J. Appl. Physiol. 67(4): 1311-1318,1989; Gerrard F. RAFFERTY, Anne Greenough, Terezia Manczur, Michael I.Polkey, M. Lou Harris, Nigel D. Heaton, Mohamed Rela, and John Moxham.Magnetic phrenic nerve stimulation to assess diaphragm function inchildren following liver transplantation. Pediatr Crit Care Med 2001,2:122-126; W. D-C. MAN, J. Moxham, and M. I. Polkey. Magneticstimulation for the measurement of respiratory and skeletal musclefunction. Eur Respir J 2004; 24: 846-860]. If one intends to stimulateonly the vagus nerve, careful positioning of the stimulator coil shouldbe undertaken in order to avoid co-stimulation of the phrenic nerve, orthe magnetic stimulation waveform may be designed to minimize the effectof any co-stimulation of the vagus and phrenic nerves [patentapplication JP2008/081479A, entitled Vagus nerve stimulation system, toYOSHIHOTO].

If it is desired to maintain a constant intensity of stimulation in thevicinity of the vagus nerve (or any other nerve or tissue that is beingstimulated), methods may also be employed to modulate the power of thestimulator in order to compensate for patient motion or other mechanismsthat would otherwise give rise to variability in the intensity ofstimulation. In the case of stimulation of the vagus nerve, suchvariability may be attributable to the patient's breathing, which mayinvolve contraction and associated change in geometry of thesternocleidomastoid muscle that is situated close to the vagus nerve(identified as 65 in FIG. 7). Methods for compensating for motion andother confounding factors were disclosed by the present applicant inco-pending application Ser. No. 12/859,568 entitled Non-InvasiveTreatment of Bronchial Constriction, to SIMON, which is herebyincorporated by reference.

Several examples follow, exemplifying therapies for neurodegenerativedisorders that involve stimulation of the vagus nerve in the neck usingmagnetic stimulation devices. However, it is understood that stimulationof the vagus nerve could also be performed at locations other than theneck [Polak T, Markulin F, Ehlis A C, Langer J B, Ringel T M, FallgatterA J. Far field potentials from brain stem after transcutaneous vagusnerve stimulation: optimization of stimulation and recording parameters.J Neural Transm. 2009 October; 116(10):1237-42]. It is also understoodthat non-invasive methods other than magnetic stimulation may also beused to stimulate the vagus nerve, in order to achieve the intendedtherapeutic effects. In particular, the non-invasive methods and devicesthat Applicant disclosed in co-pending U.S. patent application Ser. No.12/859,568 entitled Non-invasive Treatment of Bronchial Constriction, toSIMON, may also be used. It is also understood that stimulation ofnerves other than the vagus nerve may also achieve the intendedtherapeutic results, including those in the sympathetic nervous system,particularly the splenic nerve.

FIG. 8 illustrates mechanisms or pathways through which stimulation ofthe vagus nerve may be used to reduce inflammation in patients withneurodegenerative disorders. In what follows, each of the mechanisms orpathways is described in connection with treatment of particulardisorders, namely, Alzheimer's disease, Parkinson's disease, multiplesclerosis, and postoperative cognitive dysfunction and/or postoperativedelirium. However, it is understood that the treatment of otherneurodegenerative disorders using vagal nerve stimulation may also makeuse of methods involving these mechanisms or pathways. It is alsounderstood that not all of the pathways or mechanisms may be used in thetreatment of a particular patient and that pathways or mechanisms thatare not shown in FIG. 8 may also be used. Thus, particular pathways ormechanisms are invoked by the selection of particular stimulationparameters, such as current, frequency, pulse width, duty cycle, etc.Nevertheless, as an aid to understanding the applications that follow,it is useful to consider at once all the mechanisms shown in FIG. 8.

Two types of pathways are shown in FIG. 8. The pathways that stimulateor upregulate are indicated with an arrow (↓). The pathways that inhibitor downregulate are indicated with a blockage bar (⊥). Pathwaysresulting from stimulation of the vagus nerve are shown to stimulateretinoic acid 81, anti-inflammatory cytokines 82 such as TGF-beta, andneurotrophic factors 83 such as BDNF. The patient may also be treatedwith retinoic acid or some other retinoid by administering it as a drug84. For cytokines that may have both anti-inflammatory andpro-inflammatory capabilities, the retinoic acid biases such cytokinesto exhibit their anti-inflammatory potential, as shown in the pathwaylabeled as 85. Pro-inflammatory cytokines, on the other hand, promoteinflammation by pathways labeled as 86. Stimulation of the vagus nerveinhibits the release of pro-inflammatory cytokines 91 directly throughpathways that have been described by TRACEY and colleagues. The otherpathways shown in FIG. 8 to inhibit inflammation following stimulationof the vagus nerve are novel to this disclosure, and include inhibitionof inflammation via anti-inflammatory cytokine pathways 92 includingthose that inhibit the release of pro-inflammatory cytokines 93,inhibition via neurotrophic factors 94 including those that inhibit therelease of pro-inflammatory cytokines 95, and inhibition via retinoicacid pathways 96 including those that inhibit the release ofpro-inflammatory cytokines 97.

It is understood that the labels in FIG. 8 that are used for simplicityto describe the pathways actually refer to a large set of relatedpathways. For example, the box labeled as “retinoic acid” actuallyrefers to not only retinoic acid but also to a larger class ofretinoids, as well as to retinaldehyde dehydrogenases, retinoic acidreceptors (RAR), retinoid X receptors (RXR), retinoic acid responseelements (RAREs), and more generally to the retinoic acid signalingsystem of the nervous system and related pathways.

Furthermore, it is understood that the box labeled “Anti-InflammatoryCytokine, e.g., TGF-beta” can actually be placed within the box entitled“Neurotrophic Factor”, because TFG-beta is a member of the superfamilyof TGF-beta neurotrophic factors [Yossef S. Levy, Yossi Gilgun-Sherki,Eldad Melamed and Daniel Offen. Therapeutic Potential of NeurotrophicFactors in Neurodegenerative Diseases. Biodrugs 2005; 19 (2): 97-127].However, because TGF-beta is ordinarily referred to simply as acytokine, and because its anti-inflammatory competence is known to beinfluenced by retinoic acid, it was placed in a separate box to avoidundue confusion.

Example Stimulation of the Vagus Nerve to Treat Alzheimer Disease

Alzheimer (or Alzheimer's) disease (AD) is the most common cause ofdementia, affecting more than 5 million individuals in the UnitedStates. AD clinical decline and pathological processes occur gradually.Dementia is the end stage of many years of accumulation of pathologicalchanges, which begin to develop decades before the earliest clinicalsymptoms occur. A pre-symptomatic phase occurs first, in whichindividuals are cognitively normal but some have AD pathologicalchanges. This is followed by a second prodromal phase of AD, commonlyreferred to as mild cognitive impairment (MCI). The final phase in theevolution of AD is dementia, defined as impairments that are severeenough to produce loss of function.

Until recently, a definitive diagnosis of AD could only be made at theautopsy or by brain biopsy of an individual, by identifying amyloidplaques and neurofibrillary tangles (NFTs) in the association regions ofthe individual's brain, particularly in the medial aspect of thetemporal lobe. Additional evidence of AD from an individual's autopsy orbiopsy would include the presence of the following: the granulovacuolardegeneration of Shimkowicz, the neuropil threads of Braak, and neuronalloss with synaptic degeneration.

Amyloid precursor protein (APP) is a membrane protein that isconcentrated in the synapses of neurons. APP is the precursor moleculewhose proteolysis generates β-amyloid (AR), a peptide whose amyloidfibrillar form is the primary component of amyloid plaques found in thebrains of AD patients.

Tau proteins, which are abundant in the central nervous system,stabilize microtubules. When tau proteins are defective and no longerstabilize microtubules properly, they can produce dementias, includingAD. Defective tau protein will aggregate and twist into neurofibrillarytangles (NFTs), so that the protein is no longer available thestabilization of microtubules. As a result, the neuronal cytoskeletonfalls apart, contributing to neuronal malfunction and cell death.

AD begins when cells abnormally process the amyloid precursor protein(APP), which then leads to excess production or reduced clearance ofβ-amyloid (AR) in the cortex. Excess of one or more forms of AR leads toa cascade, characterized by abnormal tau protein aggregation, synapticdysfunction, cell death, and brain shrinkage. The detailed molecularmechanism of tau protein aggregation is unknown, but it is thought thatextracellular deposits of AR in the brains of AD patients promote taupolymerization.

Inflammation and the immune system play a significant role in ADpathogenesis. The inflammatory components in AD include microglia andastrocytes, the complement system, and various inflammatory mediators(including cytokines and chemokines). Microglia are the resident immunecell types of the central nervous system, and in AD, microglia may causedamage by secretion of neurotoxins. When microglia become activatedduring inflammation, they also secrete a variety of inflammatorymediators including cytokines (TNF and interleukins IL-1β and IL-6) andchemokines (macrophage inflammatory protein MIP-1a, monocytechemoattractant protein MCP-1 and interferon inducible protein IP-10)that promote the inflammatory state.

Microglia accumulate in locations that contain AR and are associatedwith the local toxicity of AR plaques. Whether the accumulated microgliacontribute to the removal or deposition of plaque is now thought todepend on the detailed microenvironment of the accumulated microglia.Microglial cell activation and migration toward β-amyloid plaquesprecede the appearance of abnormally shaped neurites and the formationof neurofibrillary tangles. It has been shown that following microglialmigration to the plaques, microglial-derived proinflammatory cytokineTNF-alpha is induced, which in turn induces accumulation of theaggregation-prone tau molecules in neurites via reactive oxygen species.[GORLOVY, P., Larionov, S., Pham, T. T. H., Neumann, H. Accumulation oftau induced in neurites by microglial proinflammatory mediators. FASEBJ. 23, 2502-2513 (2009)]. Elevated levels of TNF-alpha also induce anincreased expression of interleukin-1, which in turn increasesproduction of the precursors that may be necessary for formation ofβ-amyloid plaques and neurofibrillary tangles. Thus, the secretion ofTNF-alpha by microglia contributes to a cycle wherein tau aggregates toform tangles, R-amyloid plaques are formed, microglia aggregate to thoseplaques, and more TNF-alpha is secreted by microglia cells.

In addition to its proinflammatory functions, TNF-alpha is agliotransmitter that regulates synaptic function in neural networks. Inparticular, TNF-alpha has been shown to mediate the disruption insynaptic memory mechanisms. Etanercept, a biologic antagonist ofTNF-alpha, when delivered by perispinal administration, has been shownto improve the cognitive abilities of AD patients, even within minutesof its administration [Edward L TOBINICK and Hyman Gross. Rapidcognitive improvement in Alzheimer disease following perispinaletanercept administration. Journal of Neuroinflammation 2008, 5:2; W SueT GRIFFIN. Perispinal etanercept: Potential as an Alzheimer therapeutic.Journal of Neuroinflammation 2008, 5:3; Edward TOBINICK. Tumour NecrosisFactor Modulation for Treatment of Alzheimer's Disease Rationale andCurrent Evidence. CNS Drugs 2009; 23 (9): 713-725]. Furthermore, in apopulation of adults with rheumatoid arthritis, CHOU et al. observedthat the risk of AD was significantly reduced by TNF inhibitor therapyfor the rheumatoid arthritis, but not by other disease modifying agentsused for treatment of rheumatoid arthritis. It may therefore beconcluded that TNF may be an important component in the pathogenesis ofAD [Richard C. CHOU, Michael A. Kane, Shiva Gautam and Sanjay Ghirmire.Tumor Necrosis Factor Inhibition Reduces the Incidence of Alzheimer'sDisease in Rheumatoid Arthritis Patients. Program abstracts of theAmerican College of Rheumatology/Association of Rheumatology HealthProfessionals Scientific Meeting, Nov. 8, 2010, Atlanta Ga.,Presentation No. 640].

With the ability to better stage the progression of AD through use ofbiomarkers, treatment of AD may be justified at stages prior to actualdementia. With a better understanding of the pathogenesis of AD, thosetreatments might be directed to slowing, stopping, or reversing thepathophysiological processes underlying AD.

Biomarkers are cognitive, physiological, biochemical, and anatomicalvariables that can be measured in a patient that indicate theprogression of AD. The most commonly measured biomarkers are decreasedAβ42 in the cerebrospinal fluid (CSF), increased CSF tau, decreasedfluorodeoxyglucose uptake on PET (FDG-PET), PET amyloid imaging, andstructural MRI measures of cerebral atrophy. Biomarkers of Aβ depositionbecome abnormal early, before neurodegeneration and clinical symptomsoccur. Biomarkers of neuronal injury, dysfunction, and neurodegenerationbecome abnormal later in the disease. Cognitive symptoms are directlyrelated to biomarkers of neurodegeneration, rather than to biomarkers ofAβ deposition.

At the present time, other than physical and mental exercise, onlysymptomatic therapies for AD are available. All approved drugs for thesymptomatic treatment of AD modulate neurotransmitters—eitheracetylcholine or glutamate: cholinesterase inhibitors and partialN-methyl-D-aspartate antagonists. Psychotropic medications are also usedto treat secondary symptoms of AD such as depression, agitation, andsleep disorders.

Therapies directed to modifying AD progression itself are consideredinvestigational. These include treatment of the intense inflammationthat occurs in the brains of patients with AD, estrogen therapy, use offree-radical scavengers, therapies designed to decrease toxic amyloidfragments in the brain (vaccination, anti-amyloid antibodies, selectiveamyloid-lowering agents, chelating agents to prevent amyloidpolymerization, brain shunting to improve removal of amyloid, andbeta-secretase inhibitors to prevent generation of the A-beta amyloidfragment), and agents that may prevent or reverse excess tauphosphorylation and thereby diminish formation of neurofibrillarytangles.

However, it is increasingly recognized that a single target orpathogenic pathway for the treatment of AD is unlikely to be identified.The best strategy is a multi-target therapy that includes multiple typesof treatments [Mangialasche F, Solomon A, Winblad B, Mecocci P,Kivipelto M. Alzheimer disease: clinical trials and drug development.Lancet Neurol. 2010 July; 9(7):702-16]. Targets in that multi-targetapproach will include inflammatory pathways, and several therapeuticagents have been proposed to target them—nonsteroidal anti-inflammatorydrugs, statins, RAGE antagonists and antioxidants [Stuchbury G, Munch G.Alzheimer associated inflammation, potential drug targets and futuretherapies. J Neural Transm. 2005 March; 112(3):429-53]. Another suchagent, Etanercept, was mentioned above as targeting TNF-alpha, but itsuse has the disadvantage that because it does not pass the blood-brainbarrier (BBB), its administration is via a painful spinal route or viaan experimental method to get through the BBB [U.S. Pat. No. 7,640,062,entitled Methods and systems for management of alzheimer's disease, toSHALEV]. One TNF-inhibitor that does not have this disadvantage isthalidomide [Tweedie D, Sambamurti K, Greig N H: TNF-alpha Inhibition asa Treatment Strategy for Neurodegenerative Disorders: New DrugCandidates and Targets. Curr Alzheimer Res 2007, 4(4):375-8]. However,thalidomide is well known by the public to cause birth defects, and in asmall trial, its use did not appear to improve cognition in AD patients[Peggy PECK. IADRD: Pilot Study of Thalidomide for Alzheimer's DiseaseFails to Detect Cognitive Benefit but Finds Effect on TNF-alpha.Doctor's Guide Global Edition, Jul. 26, 2002]. There is therefore a needin the art for new therapies that target TNF-alpha, including itsphysiological activity for a given amount, as a component of amulti-target approach to treating AD

In 2002, it was reported that electrical stimulation of the vagus nervehas a beneficial effect on cognition in patients with AD [Sjögren M J,Hellström P T, Jonsson M A, Runnerstam M, Silander H C, Ben-Menachem E.Cognition-enhancing effect of vagus nerve stimulation in patients withAlzheimer's disease: a pilot study. J Clin Psychiatry. 2002 November;63(11):972-80]. The rationale for the trial was that vagus nervestimulation had previously been found to enhance the cognitive abilitiesof patients that were undergoing vagus nerve stimulation for otherconditions such as epilepsy and depression, as well cognitive abilitiesobserved in animal studies. Results concerning the AD patients' improvedcognitive abilities over a longer period of time, along with improvementin tau protein of cerebrospinal fluid, were subsequently reported[Merrill C A, Jonsson M A, Minthon L, Ejnell H, C-son Silander H,Blennow K, Karlsson M, Nordlund A, Rolstad S, Warkentin S, Ben-MenachemE, Sjögren M J. Vagus nerve stimulation in patients with Alzheimer'sdisease: Additional follow-up results of a pilot study through 1 year. JClin Psychiatry. 2006 August; 67(8):1171-8]. Stimulation of the vagusnerve to treat dementia might be more effective than stimulation ofnerves found in locations such as the spine, forehead, and earlobes[Cameron M H, Lonergan E, Lee H. Transcutaneous Electrical NerveStimulation (TENS) for dementia. Cochrane Database of Systematic Reviews2003, Issue 3. Art. No.: CD004032. (2009 update)]. The method of usingvagal nerve stimulation to treat AD had been disclosed earlier in U.S.Pat. No. 5,269,303, entitled Treatment of dementia by nerve stimulation,to WERNICKE et al., but neither that patent nor the clinical trialsproposed any physiological intermediary through which vagal nervestimulation may result in clinical improvement to AD patients.

It has been proposed that electrical stimulation of the vagus nerve mayattenuate an inflammatory response. In particular, methods involvingelectrical stimulation of the vagus nerve have been disclosed forattenuating or inhibiting the release of the pro-inflammatory cytokineTNF-alpha, including AD as one disease in a long list of diseasesinvolving inflammation [U.S. Pat. No. 6,610,713 and U.S. Pat. No.6,838,471, entitled Inhibition of inflammatory cytokine production bycholinergic agonists and vagus nerve stimulation, to TRACEY; Kevin J.TRACEY. The inflammatory reflex. Nature 420 (2002): 853-859; Kevin J.TRACEY. Physiology and immunology of the cholinergic anti-inflammatorypathway. J. Clin. Invest. 117 (2007):289-296]. It has also been proposedthat electrical stimulation of nerves of the sympathetic nervous system(particularly the splenic nerve) may also attenuate an inflammatoryresponse, by attenuating or inhibiting the release of TNF-alpha,including AD as a one disease in a long list of diseases involvinginflammation [U.S. Pat. No. 7,769,442, entitled Device and method forinhibiting release of pro-inflammatory mediator, to SHAFER]. PROLO etal. noted the above-mention vagal nerve stimulation investigations andpredicted that interventions based on attenuation of inflammation wouldbe useful for the treatment of AD [Paolo PROLO, Francesco Chiappelli,Alberto Angeli, Andrea Dovio, Maria Luisa Sartori, Fausto Fanto, NegoitaNeagos, Ercolano Manfrini. Putative Neurolmmune Mechanisms inAlzheimer's Disease: Modulation by Cholinergic Anti-Inflammatory Reflex(CAIR). International Journal of Integrative Biology 2007, Vol 1 (No.2):88-95].

However, as noted above, TNF-alpha is involved in more than inflammationin AD [Ian A. CLARK, Lisa M. Alleva and Bryce Vissel. The roles of TNFin brain dysfunction and disease. Pharmacology & Therapeutics, 128(Issue 3, December 2010): 519-548]. It is also a gliotransmitter thatregulates synaptic function in neural networks [Gertrudis PEREA andAlfonso Araque. GLIA modulates synaptic transmission. Brain ResearchReviews. 63 (Issues 1-2, May 2010):93-102]. In that capacity, TNF-alphahas been shown to mediate the disruption in synaptic memory mechanisms.None of the above-mentioned citations have proposed that stimulation ofthe vagus nerve modulates the capacity of TNF-alpha to function as agliotransmitter, which can be released from any glial cell, includingoligodendrocytes, astrocytes, and microglia. Such modulation in capacitycan be due to a change in the amount of TNF-alpha or in the activity ofa given amount of TNF-alpha or in the activity of the cells betweenwhich TNF-related gliotransmission occurs. In fact, the above-mentionedcitations are concerned only with the attenuation or inhibition of therelease of TNF-alpha as a pro-inflammatory mediator, but not with itsdegradation or modification or with changes in its activity for a givenamount.

Stimulation of the vagus nerve may also antagonize the pro-inflammatorycapabilities of TNF-alpha and other pro-inflammatory cytokines throughmechanisms that are different from those proposed by TRACEY andcolleagues. In particular, it has been observed that stimulation of thevagus nerve may enhance the release of retinoic acid (RA) from nervelocations that produce RA from retinaldehyde using retinaldehydedehydrogenases [van de PAVERT SA, Olivier B J, Goverse G, Vondenhoff MF, Greuter M, Beke P, Kusser K, Hopken U E, Lipp M, Niederreither K,Blomhoff R, Sitnik K, Agace W W, Randall T D, de Jonge W J, Mebius R E.Chemokine CXCL13 is essential for lymph node initiation and is inducedby retinoic acid and neuronal stimulation. Nat Immunol. 10(11, 2009):1193-1199]. The retinoic acid so released may directly inhibit therelease or functioning of proinflammatory cytokines, which would be ananti-pro-inflammatory mechanism that is distinct from the one proposedby TRACEY and colleagues [Malcolm Maden. Retinoic acid in thedevelopment, regeneration and maintenance of the nervous system. NatureReviews Neuroscience 8 (2007), 755-765]. Because RA strongly suppressesthe production of IL6, inhibits amyloid-beta-induced TNF-alphaproduction, and inhibits expression of inducible NO synthase (iNOS) inactivated microglia, the release of RA following stimulation of thevagus nerve will also serve to inhibit inflammation [K. SHUDO, H.Fukasawa, M. Nakagomi and N. Yamagata. Towards Retinoid Therapy forAlzheimer's Disease. Current Alzheimer Research, 2009, 6, 302-311].Retinoic acid can also regulate the expression of the tau protein, andin particular the level of phosphorylated forms of tau [Andrea MALASPINAand Adina T. Michael-Titus. Is the modulation of retinoid and retinoidassociated signaling a future therapeutic strategy in neurologicaltrauma and neurodegeneration? J. Neurochem. (2008) 104, 584-595].Furthermore, stimulation of nerves to release retinoic acid or activateits receptors may also promote the clearance of beta amyloids in AD byRA activation of the heterodimeric complex formed by PPAR-RXR [CamachoI. E., Serneels L., Spittaels K., Merchiers P., Dominguez D. and DeStrooper B. Peroxisome-proliferator-activated receptor gamma induces aclearance mechanism for the amyloid-beta peptide. J. Neurosci. 24(2004), 10908-10917].

The cytokine TGF-beta acts in a highly contextual manner, and dependingon cell type and environment, TGF-beta may promote cell survival orinduce apoptosis, stimulate cell proliferation or inducedifferentiation, and initiate or resolve inflammation. In the presenceof RA, TGF-beta is biased towards anti-inflammation, so the release ofRA following vagal nerve stimulation may inhibit inflammation by thatpro-anti-inflammatory mechanism as well [Tony Wyss-Coray. TGF-betaPathway as a Potential Target in Neurodegeneration and Alzheimer's.Current Alzheimer Research, 3 (2006): 191-195]. Treating the patientwith oral retinoic acid may also promote an anti-inflammatory bias forTGF-beta. Furthermore, vagal nerve stimulation may also stimulate theproduction of the TGF-beta that can act as an anti-inflammatory agent[CORCORAN, Ciaran; Connor, Thomas J; O'Keane, Veronica; Garland, MalcolmR. The effects of vagus nerve stimulation on pro- and anti-inflammatorycytokines in humans: a preliminary report. Neuroimmunomodulation 12 (5,2005): 307-309].

TGF-beta is a member of the TGF-beta superfamily of neurotrophicfactors. Neurotrophic factors serve as growth factors for thedevelopment, maintenance, repair, and survival of specific neuronalpopulations, acting via retrograde signaling from target neurons byparacrine and autocrine mechanisms. Nerve growth factor (NGF) is themost widely examined neurotrophin in experimental models of AD, and ofall the factors tested, NGF appears to be the most effective inimproving the survival and maintenance of cholinergic neurons. It istherefore considered to be a promising therapeutic agent for AD [YossefS. LEVY, Yossi Gilgun-Sherki, Eldad Melamed and Daniel Offen.Therapeutic Potential of Neurotrophic Factors in NeurodegenerativeDiseases. Biodrugs 2005; 19 (2): 97-127; Mark H. TUSZYNSKI. Nerve GrowthFactor Gene Therapy in Alzheimer Disease. Alzheimer Dis Assoc Disord 21(2, 2007): 179-189]. However, major problems in using neurotrophicfactors for therapy are their inability to cross blood-brain-barrier,adverse effects resulting from binding to the receptor in other organsof the body and their low diffusion rate.

It is known that vagal nerve stimulation and transcranial magneticstimulation can increase the levels of at least one neurotrophic factorin the brain, brain-derived neurotrophic factor (BDNF), which has beenstudied extensively in connection with the treatment of depression.However, it has never been suggested that vagal nerve stimulation may beutilized to increase BDNF levels in AD patients. BDNF is known to bereduced in AD brains, and the introduction of BDNF into the brain ofanimal models of AD promotes regeneration [Alan H NAGAHARA et al.Neuroprotective effects of brain-derived neurotrophic factor in rodentand primate models of Alzheimer's disease. Nat Med. 15(3, 2009):331-337]. Vagal nerve stimulation may likewise promote the expression ofother neurotrophic factors such as NGF, which circumvents the problem ofblood-brain barrier blockage [Follesa P, Biggio F, Gorini G, Caria S,Talani G, Dazzi L, Puligheddu M, Marrosu F, Biggio G. Vagus nervestimulation increases norepinephrine concentration and the geneexpression of BDNF and bFGF in the rat brain. Brain Research 1179(2007): 28-34; Biggio F, Gorini G, Utzeri C, 011a P, Marrosu F,Mocchetti I, Follesa P. Chronic vagus nerve stimulation induces neuronalplasticity in the rat hippocampus. Int J. Neuropsychopharmacol. 12(9,2009):1209-21; Roberta Zanardini, Anna Gazzoli, Mariacarla Ventriglia,Jorge Perez, Stefano Bignotti, Paolo Maria Rossini, Massimo Gennarelli,Luisella Bocchio-Chiavetto. Effect of repetitive transcranial magneticstimulation on serum brain derived neurotrophic factor in drug resistantdepressed patients. Journal of Affective Disorders 91 (2006) 83-86].Patent application US20100280562, entitled Biomarkers for monitoringtreatment of neuropsychiatric diseases, to PI et al, disclosed themeasurement of BDNF following vagal nerve stimulation. However, thatapplication is concerned with the search for biomarkers involving thelevels of BDNF, rather than a method for treating a neurodegenerativedisease using vagal nerve stimulation.

Magnetic stimulation of AD patients has been performed, but its use hasbeen intended to affect cognitive skills using transcranial magneticstimulation [Mamede de Carvalho, Alexandre de Mendonça, Pedro C.Miranda, Carlos Garcia and Maria Lourdes Sales Luis. Magneticstimulation in Alzheimer's disease. Journal of Neurology 244 (1997, 5):304-307; Cotelli M, Manenti R, Cappa S F, Zanetti O, Miniussi C.Transcranial magnetic stimulation improves naming in Alzheimer diseasepatients at different stages of cognitive decline. Eur J. Neurol. 15(12,2008):1286-92; Guse B, Falkai P, Wobrock T. Cognitive effects ofhigh-frequency repetitive transcranial magnetic stimulation: asystematic review. J Neural Transm. 117(1, 2010):105-22].

Accordingly, methods are disclosed here to treat AD patients, preferablyas part of a multi-target therapy. The foregoing review of AD disclosedsix novel mechanisms by which stimulation of the vagus nerve may be usedto treat AD: (1) stimulate the vagus nerve in such a way as to enhancethe availability or effectiveness of TGF-beta or other anti-inflammatorycytokines; (2) stimulate the vagus nerve in such a way as to enhance theavailability or effectiveness of retinoic acid; (3) stimulate the vagusnerve in such a way as to promote the expression of the neurotrophicfactors such as BDNF; (4) stimulate the vagus nerve to modulate thecapacity of TNF-alpha to function as a gliotransmitter, includingmodulating the activity of the cells between which TNF-relatedgliotransmission occurs; (5) stimulate the vagus nerve in such a way asto suppress the release or effectiveness of pro-inflammatory cytokines,through a mechanism that is distinct from the one proposed by TRACEY andcolleagues; (6) stimulate the vagus nerve to modulate the degradation ofTNF-alpha, and/or modify the activity of existing TNF-alpha molecules asa pro-inflammatory mediator.

In the preferred embodiment, the method stimulates the vagus nerve asindicated in FIGS. 6 and 7, using the toroidal magnetic stimulationdevice that is disclosed herein. The position and angular orientation ofthe device are adjusted about that location until the patient perceivesstimulation when current is passed through the stimulator coils. Theapplied current is increased gradually, first to a level wherein thepatient feels sensation from the stimulation. The power is thenincreased, but is set to a level that is less than one at which thepatient first indicates any discomfort. Straps, harnesses, or frames areused to maintain the stimulator in position (not shown in FIG. 6 or 7).The stimulator signal may have a frequency and other parameters that areselected to influence the therapeutic result. For example, a pulse widthmay be from about 0.01 ms to 500.0 ms, typically 200 ms. The pulses maybe delivered at a frequency of 0.5 to 500 Hz., typically 20 Hz. Thestimulation may be performed for 1 to 200 minutes, typically for 30minutes. Typically, the treatment is performed repeatedly, e.g., once aweek for six months. However, parameters of the stimulation may bevaried in order to obtain a beneficial response, as indicated, forexample, by the measurement of levels and/or activities of TGF-beta,neurotrophic factors, retinoic acid, and/or TNF-alpha in the patient'speripheral circulation and/or in the patient's cerebrospinal fluid,during and subsequent to each treatment.

Example Stimulation of the Vagus Nerve to Treat Parkinson's Disease

Parkinson's disease (PD) is a chronic neurodegenerative disease that ischaracterized by problems with movement, particularly tremor at rest,slowness of gait, joint and muscle rigidity, and unstable posture. Thedisease is also commonly accompanied by cognitive, autonomic, andsensory dysfunctions. PD symptoms result from dopamine insufficiency indopaminergic neurons of the substantia nigra and other portions of themidbrain. In PD, neuromelanin-pigmented, dopamine-secreting neurons inthose regions die, at locations where there is an abnormal accumulationand aggregation of misfolded alpha-synuclein protein in the form ofso-called Lewy bodies.

Definite diagnosis of PD is made only at autopsy with a finding ofsubstantial nerve cell depletion with accompanying gliosis in thesubstantia nigra, of at least one Lewy body in the substantia nigra orin the locus coeruleus, and of no pathological evidence for otherdiseases that produce symptoms of Parkinsonism. Diagnosis of PD basedupon symptoms alone is considered to be only probable, with up to 20% ofthe probable PD diagnoses not confirmed after autopsy. The onset andprogression of probable PD in an individual is commonly quantified usinga scoring device known as the Unified Parkinson's Disease Rating Scale(UPDRS), which incorporates considerations used to diagnose PD. Thescoring of symptoms follows standard neurological examination practice,in which finding of the following contribute to the diagnosis ofPD—tremor (especially if more pronounced at rest); slowing of motion andmuscle rigidity; onset of symptoms on only one side of the body; andimprovement with administration of levodopa [J JANKOVIC. Parkinson'sdisease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry79 (2008):368-376; Christopher G. GOETZ et al. Movement DisorderSociety-Sponsored Revision of the Unified Parkinson's Disease RatingScale (MDS-UPDRS): Scale Presentation and Clinimetric Testing Results.Movement Disorders 23 (No. 15, 2008): 2129-2170].

Currently, there are no laboratory tests that can confirm a neurologicaldiagnosis of probable PD. Blood and cerebrospinal fluid tests of PDpatients are often normal, electroencephalography is not able to detectPD, and the MRI and CAT scans of PD patients appear normal. However,experimental biomarkers for diagnosing PD are available [A. W. Michell,S. J. G. Lewis, T. Foltynie and R. A. Barker. Biomarkers and Parkinson'sdisease. Brain (2004), 127, 1693-1705; Manuel B. Graeber. Biomarkers forParkinson's disease. Experimental Neurology 216 (2009) 249-253].

PD is the second most common neurodegenerative disease after Alzheimer'sdisease and is the most common movement disorder. Some movementdisorders resemble PD but belong to a more general category of disorderreferred to as Parkinsonian syndrome or Parkinsonism. Other movementdisorders may involve neurodegeneration at some point in theirpathogenesis, including multiple system atrophy, progressivesupranuclear palsy, corticobasal degeneration, tremor, dystonia(including torticollis, spasmodic dysphonia and blepharospasm), restlessleg syndrome, tic and Tourette syndrome, chorea, spasticity and tardivedyskinesia. It is understood that the methods disclosed herein for thetreatment of PD may be used to treat such other movement disorders aswell.

PD usually appears in people between 40 and 70 years of age, with theincidence of PD peaking in people in their sixties. More than onemillion individuals in the North America have PD, and in industrializedsocieties, greater than 1% of the population over the age of 65 yearshave the disease. Increasing age beyond 60 years is a strong risk factorfor PD. Currently, there is no clear evidence that PD is foundpreferentially in a particular sex or geographical location. Exposure tothe neurotoxin MPTP causes permanent symptoms that are similar to thosein PD, and exposure to toxic chemicals such as pesticides (e.g.,rotenone), herbicides (e.g., paraquat), and fungicides (e.g., maneb)greatly increase the risk of developing PD. Only 5-15% of the cases ofPD are related to the patient having a predisposing gene, but some suchgenes lead to early-onset PD. Use of tobacco, coffee, non-steroidalanti-inflammatory drugs and calcium channel blocker drugs have beenfound to protect against PD. [Lonneke M L DELAU, Monique M B Breteler.Epidemiology of Parkinson's disease. Lancet Neurol 5 (2006): 525-35;SHIN, J.-H., V. L. Dawson, T. M. Dawson, SnapShot: Parkinson's diseasepathogenesis. Cell 139 (2009):440-440].

BRAAK and colleagues present evidence that PD ordinarily begins in thedorsal motor nucleus of the vagus nerve (in the medulla) and not in themidbrain dopaminergic neurons as has been generally assumed.Furthermore, since this site is connected to the periphery by the vagusnerve, they propose that toxic factors enters the central nervous systemvia the vagus nerve, and the pathological process then progresses up theneuroaxis, during which components of the olfactory, autonomic, limbic,and somatomotor systems become progressively involved [BRAAK H, Bohl JR, Muller C M, Rub U, de Vos R A, Del Tredici K., Stanley Fahn Lecture2005: The staging procedure for the inclusion body pathology associatedwith sporadic Parkinson's disease reconsidered. Mov Disord 2006;21(12):2042-51]. Accordingly, methods for preventing or treating PD areto stimulate the vagus nerve in such a way as to prevent toxins(environmental toxin, virus, or alpha-synuclein clusters) from reachingthe dorsal motor nucleus of the vagus nerve, to serve as an antidote totoxins that have already reached that location, and to prevent thepathology from progressing up the neuroaxis.

The pathophysiological origins of dopaminergic nerve depletion in thesubstantia nigra of PD patients are thought to involve mitochondrialdysfunction, oxidative and nitrosative stress, and impairment of theubiquitinproteasome system (UPS) and the autophagy-lysosome pathway(ALP), with attendant aberrant protein handling. Nerve depletion occursin dopamine producing cells of the substantia nigra because those cellare uniquely susceptible to damage, as a result of their high energyrequirements and their expression of a unique Cav 1.3 calcium channelprotein. The calcium channel protein causes sustained elevations incytosolic calcium concentration, particularly in dendrites, whichstimulates mitochondrial respiratory metabolism and generates reactiveoxygen species (ROS). Generation of ROS or damage from environmentaltoxins leads to inhibition of the first enzyme complex of themitochondrial electron-transfer chain (mitochondrial complex I). Forexample, the Parkinson-producing toxin MPTP specifically inhibitsmitochondrial complex I. This leads to eventual depolarization of themitochondrial membrane and opening of the mitochondrial permeabilitytransition pore. A by-product of such mitochondrial impairment isincreased production of more ROS, producing a vicious cycle of moreoxidative damage within the neurons of PD patients [Chan C S, Guzman JN, Ilijic E, Mercer J N, Rick C, Tkatch T, Meredith G E, Surmeier D J(2007) ‘Rejuvenation’ protects neurons in mouse models of Parkinson'sdisease. Nature 447: 1081-1086].

Alpha-synuclein (alpha-SN) is a cytoplasmic protein that is highlyexpressed in dopaminergic neuronal cells and that interacts withpre-synaptic membranes, suggesting that its function is to regulatesynaptic vesicle pools, including control of dopamine levels. As notedabove, alpha-SN deposits in the form of Lewy Bodies are a definingcharacteristic of PD. Oxidation and nitration of alpha-SN in theenvironment of dysfunctional mitochondria lead to the formation ofalpha-SN aggregates and the stabilization of assembled alpha-SNfilaments. Such abnormal alpha-SN might also damage mitochondriadirectly, contributing to even greater oxidative stress andmitochondrial dysfunction. The conversion of alpha-SN from solublemonomers to aggregated amyloid-like insoluble forms is a key event in PDpathogenesis.

Protein mishandling due to dysfunction in the ubiquitinproteasome system(UPS) and the autophagy-lysosome pathway (ALP) are major pathwaysleading to neuronal degeneration in PD. The UPS pathway targets andrapidly destroy misfolded proteins in cells, through attachment ofubiquitin to target proteins. The ubiquitin tag serves as a signal fortheir degradation by a proteasome, which is an abundant ATP-dependentprotease. The second pathway is autophagy, which is a catabolic processinvolving the degradation of a cell's own components through lysosomalmachinery. It comprises several types: macroautophagy, microautophagy,and chaperone-mediated autophagy. Although the UPS and ALP pathways mayclear damaged cell components in early stages of PD, eventually they maythemselves become damaged and contribute to the progression of PD.

Abnormal alpha-SN is thought to cause UPS dysfunction through bindingand inhibiting the 20/26S proteasome, and abnormal or aggregated formsof alpha-SN may also overwhelm the degradative capacity of theproteasome, leading to UPS impairment beyond that which is attributableto oxidation of UPS components.

Once the UPS has become dysfunctional, autophagy is upregulated as acompensatory mechanism for degrading aggregated, misfolded and abnormalproteins. However, lysosomal malfunction has been found to accompanyalpha-SN aggregation, supporting the view that ALP dysfunction is animportant mechanism of neurodegeneration. Furthermore, dysfunction ofthe ALP is thought to occur naturally as a consequence of aging, so thatclearance of aggregating alpha-SN might fail in the cells of elderlyindividuals irrespective of whether the abnormal alpha-SN promotes ALPdysfunction.

Autophagy has a dual role: to promote cell survival through removal ofabnormal cellular components, and to promote cell death whenintracellular damage is beyond repair. Inappropriate or prolongedactivation of autophagy may therefore lead to the complete death anddestruction of some cells in PD. Other mechanisms for the death of thedefective dopamine-producing cells include caspase-dependent andcaspase-independent pathways, endoplasmic-reticulum stress, neuronalnitric oxide synthase (nNOS) activation, DNA damage, poly(ADP-ribose)polymerase (PARP) activation, and GAPDH modification [Dale E. BREDESEN,Rammohan V. Rao and Patrick Mehlen. Cell death in the nervous system.Nature 443(7113, 2006):796-802; Tianhong PAN, Seiji Kondo, Weidong Le,Joseph Jankovic. The role of autophagy-lysosome pathway inneurodegeneration associated with Parkinson's disease. Brain 131 (2008):1969-1978].

Another mechanism leading to the death of dopamine-producing cells in PDis inflammatory, through microglial activation. The activation beginswith microglia detecting stimulatory signaling molecules such as theactive form of MMP-3, alpha-SN and neuromelanin that have leaked fromintact cells or that are extracellular after the destruction ofdopamine-producing cells by mechanisms that were described above.Activated microglia cause dopamine neuronal degeneration either bysuperoxide, NO and other proinflammatory cytokines or by directphagocytosis against neurons that are in the process of becomingdysfunctional or even normal (bystander) neurons. Products derived frommicroglia and astrocytes act in a combinatorial manner to promoteneurotoxicity. The inflammatory response becomes a vicious cycle becauseadditional microglial activating factors are leaked or released from thecells that are attacked during the inflammation [Kim Y S, Joh T H.Microglia, major player in the brain inflammation: their roles in thepathogenesis of Parkinson's disease. Exp Mol Med 38 (2006): 333-347].

Neutralizing the proinflammatory cytokine tumor necrosis factor(TNF-alpha) has been found to reduce nigral degeneration in an animalmodel of PD. [Melissa K. McCOY, Terina N. Martinez, Kelly A. Ruhn, DavidE. Szymkowski, Christine G. Smith, Barry R. Botterman Keith E. Tanseyand Malù G. Tansey. Blocking Soluble Tumor Necrosis Factor Signalingwith Dominant-Negative Tumor Necrosis Factor Inhibitor Attenuates Lossof Dopaminergic Neurons in Models of Parkinson's Disease. The Journal ofNeuroscience 26(37, 2006):9365-9375]. U.S. Pat. No. 6,610,713 and U.S.Pat. No. 6,838,471, entitled Inhibition of inflammatory cytokineproduction by cholinergic agonists and vagus nerve stimulation, toTRACEY, also suppress the release of proinflammatory cytokines, such asTNF-alpha, by vagal nerve stimulation. The methods described in thosepatents might therefore substitute for the anti-TNF treatment that wasused by McCOY and colleagues. However, there is no mention or suggestionthat the methods described in those patents are intended to modulate theactivity of anti-inflammatory cytokines such as TGF-beta or toantagonize TNF-alpha by some other mechanism. One such mechanisminvolves the release of retinoic acid from cells [Malcolm Maden.Retinoic acid in the development, regeneration and maintenance of thenervous system. Nature Reviews Neuroscience 8 (2007), 755-765] and isdiscussed below.

Under normal physiologic conditions, microglia are maintained quiescentby the coordinate action of neurons and astrocytes. Astrocytes are ableto suppress microglial activation by releasing TGF-beta or IL-10[Vincent V A, Tilders F J, Van Dam A M. Inhibition of endotoxin-inducednitric oxide synthase production in microglial cells by the presence ofastroglial cells: a role for transforming growth factor beta. Glia. 1997March; 19(3):190-8]. TGF-beta is also produced by, and promotes thesurvival of, neurons in the substantia nigra and the striatum [KerstinKrieglstein. Factors promoting survival of mesencephalic dopaminergicneurons. Cell Tissue Res (2004) 318: 73-80].

The orphan nuclear receptor Nurr1 also inhibits expression ofproinflammatory neurotoxic mediators in microglia and astrocytes. Aheterodimer between the retinoid X receptor and Nurr1 also rescuesdopamine-producing neurons from degeneration [Stina Friling, MariaBergsland and Susanna Kjellander. Activation of Retinoid X Receptorincreases dopamine cell survival in models for Parkinson's disease. BMCNeuroscience 2009, 10:146; Kaoru Saijo, Beate Winner, Christian T.Carson, Jana G. Collier, Leah Boyer, Michael G. Rosenfeld, Fred H. Gage,and Christopher K. Glass. A Nurr1/CoREST Pathway in Microglia andAstrocytes Protects Dopaminergic Neurons from Inflammation-InducedDeath. Cell 137, 47-59, Apr. 3, 2009].

This implicates retinoic acid in the response to inflammatory and otherdamage through the following mechanism. Retinoic acid acts by binding toheterodimers of the retinoic acid receptor (RAR) and the retinoid Xreceptor (RXR), which then bind to retinoic acid response elements(RAREs) to activate transcription in the regulatory regions of targetsurvival and repair genes. Retinoic acid signaling is also involved innormal nigrostriatal functioning, as evidenced by the fact thatdisulphiram, which blocks the synthesis of retinoic acid, inducesParkinsonism by producing lesions. The dopaminergic neurons of thenigrostriatal system contain high levels of retinaldehyde dehydrogenasethat generate retinoic acid in the axon terminals, which in turn acts onneurotransmission in an autocrine fashion or on the striatal cells in aparacrine fashion [Malcolm Maden. Retinoic acid in the development,regeneration and maintenance of the nervous system Nature ReviewsNeuroscience 8 (2007), 755-765].

Thus, the enhanced availability of TGF-beta and retinoic acid arethought to have anti-inflammatory effects in PD, and both have beenreported to be enhanced by stimulation of the vagus nerve [CORCORAN,Ciaran; Connor, Thomas J; O'Keane, Veronica; Garland, Malcolm R. Theeffects of vagus nerve stimulation on pro- and anti-inflammatorycytokines in humans: a preliminary report. Neuroimmunomodulation 12 (5,2005): 307-309; van de PAVERT S A, Olivier B J, Goverse G, Vondenhoff MF, Greuter M, Beke P, Kusser K, Höpken U E, Lipp M, Niederreither K,Blomhoff R, Sitnik K, Agace W W, Randall T D, de Jonge W J, Mebius R E.Chemokine CXCL13 is essential for lymph node initiation and is inducedby retinoic acid and neuronal stimulation. Nat Immunol. 10(11, 2009):1193-1199].

TGF-beta is a member of the TGF-beta superfamily of neurotrophicfactors. Neurotrophic factors serve as growth factors for thedevelopment, maintenance, repair, and survival of specific neuronalpopulations, acting via retrograde signaling from target neurons byparacrine and autocrine mechanisms. Other neurotrophic factors, such asglial cell line-derived neurotrophic factor (GDNF) and neurturin alsostrongly promote the survival of dopamine-producing neurons. However,major problems in using neurotrophic factors for therapy are theirinability to cross blood-brain-barrier, adverse effects resulting frombinding to the receptor in other organs of the body and their lowdiffusion rate. A recently discovered neurotrophic factor, mesencephalicastrocyte-derived neurotrophic factor (MANF), is able to diffuse morerapidly but is also unable to cross the blood-brain barrier [Yossef S.Levy, Yossi Gilgun-Sherki, Eldad Melamed and Daniel Offen. TherapeuticPotential of Neurotrophic Factors in Neurodegenerative Diseases.Biodrugs 2005; 19 (2): 97-127; Voutilainen M H, Bäck S, Pörsti E,Toppinen L, Lindgren L, Lindholm P, Peränen J, Saarma M, Tuominen R K.Mesencephalic Astrocyte-Derived Neurotrophic Factor Is Neurorestorativein Rat Model of Parkinson's Disease. The Journal of Neuroscience, Jul.29, 2009, 29(30):9651-9659].

However, it is known that vagal nerve stimulation and transcranialmagnetic stimulation can increase the levels of at least oneneurotrophic factor in the brain, brain-derived neurotrophic factor(BDNF), which has been studied extensively in connection with thetreatment of depression. It is therefore possible that vagal nervestimulation may likewise promote the expression of the neurotrophicfactors such as GDNF and MANF that are known to promote the survival ofdopamine-producing cells in PD, thereby circumventing the problem ofblood-brain barrier blockage [Follesa P, Biggio F, Gorini G, Caria S,Talani G, Dazzi L, Puligheddu M, Marrosu F, Biggio G. Vagus nervestimulation increases norepinephrine concentration and the geneexpression of BDNF and bFGF in the rat brain. Brain Research 1179(2007): 28-34; Biggio F, Gorini G, Utzeri C, 011a P, Marrosu F,Mocchetti I, Follesa P. Chronic vagus nerve stimulation induces neuronalplasticity in the rat hippocampus. Int J. Neuropsychopharmacol. 12(9,2009):1209-21; Roberta Zanardini, Anna Gazzoli, Mariacarla Ventriglia,Jorge Perez, Stefano Bignotti, Paolo Maria Rossini, Massimo Gennarelli,Luisella Bocchio-Chiavetto. Effect of repetitive transcranial magneticstimulation on serum brain derived neurotrophic factor in drug resistantdepressed patients. Journal of Affective Disorders 91 (2006) 83-86].Patent application US20100280562, entitled Biomarkers for monitoringtreatment of neuropsychiatric diseases, to PI et al, disclosed themeasurement of GDNF following vagal nerve stimulation. However, thatapplication is concerned with the search for biomarkers involving thelevels of GDNF, rather than a method for treating a neurodegenerativedisease using vagal nerve stimulation.

It is known that the levels of BDNF are rapidly regulated by sensoryinput during development and in adulthood, particularly the presence orabsence of bright light [Eero CASTREN, Francisco Zafra, Hans Thoenen,and Dan Lindholm. Light regulates expression of brain-derivedneurotrophic factor mRNA in rat visual cortex. Proc. Nad. Acad. Sci. USA89 (1992): 9444-9448]. The levels of other neurotrophic factors may alsobe regulated by sensory input. Accordingly, it may be possible toenhance the effect of vagal nerve stimulation on the levels ofneurotrophic factors by simultaneously presenting the waveform of thevagal nerve stimulation to the patient by a second route, in the form ofbright light that is fluctuating in intensity with the vagal stimulationwaveform. The bright light waveform may be presented without any delay,or it may be presented after a delay such that the vagal and lightwaveforms can best entrain one another within the patient's brain.Considering that bright light therapy and vagal nerve stimulation areestablished treatments for depression, such a novel combined therapy maybe most successful for treating depression. However, bright lighttherapy has also been used successfully to treat PD, and its successwith PD patients may be attributable to the regulation of neurotrophicfactors in addition to BDNF [Sebastian Paus, Tanja Schmitz-Hubsch,Ullrich Wullner, Antje Vogel, Thomas Klockgether and Michael Abele.Bright Light Therapy in Parkinson's Disease: A Pilot Study. MovementDisorders 22(10, 2007): 1495-1498]. It is understood that other forms ofsensory input may also be used in place of, or in addition to, brightlight, e.g., audio or tactile input that is presented with the waveformof the vagal nerve stimulator.

To understand how PD symptoms of abnormal movement relate todopaminergic nerve depletion in the substantia nigra, it is necessary toappreciate how the substantia nigra connects functionally andneuroanatomically to regions of the brain that control movement.Basically, dopaminergic depletion in PD disrupts corticostriatalneuroelectrical balance, leading to increased activity in an indirectcircuit and reduced activity in a direct circuit. Those imbalancedcorticostriatal connections result in excessive thalamic inhibition,which leads to suppression of the cortical motor system, resulting inakinesia, rigidity, and tremor; and inhibitory descending projection tobrain-stem locomotor areas contribute to abnormalities of gait andposture [Lang A E, Lozano A M. Parkinson's disease. Second of two parts.N Engl J Med 339 (No. 16, 1998): 1130-1143; OBESO JA, Rodriguez-Oroz MC, Benitez-Temino B, et al. Functional organization of the basalganglia: therapeutic implications for Parkinson's disease. Mov. Disord.23 (Suppl 3, 2008): S548-59]. That understanding provides a rationalefor the PD treatments involving deep brain stimulation or ablation thatare summarized below.

Currently there is no cure for PD, but therapies are available to treatits symptoms and retard its progression. The drug levodopa (L-DOPA) isthe most commonly used treatment. It is transformed into dopamine indopaminergic neurons and therefore compensates for the lack of dopaminein the substantia nigra. Because L-DOPA may be metabolized beforecrossing the blood-brain barrier, its meta bolite(s) may causesignificant side-effects by virtue of their effects outside the brain.Therefore, peripheral dopa decarboxylase inhibitors (carbidopa andbenserazide) are often co-administered with L-DOPA to reduce the sideeffects. Furthermore, administered L-DOPA inhibits the endogenousformation of dopamine, so its administration eventually becomescounterproductive, such that the PD patient exhibits periods ofunresponsiveness to L-DOPA (the so-called “off” periods). At that point,dopamine agonists may be administered, which activate dopamine receptorseven in the absence of dopamine. The dopamine agonists includebromocriptine, pergolide, pramipexole, ropinirole, piribedil,cabergoline, apomorphine, and lisuride. In late PD they are useful forreducing the “off” periods. They may also be administered as an initialtreatment depending on the age of the patient, before using L-DOPA. Inlieu of dopamine agonists, MAO-B inhibitors (selegiline and rasagiline)may also be administered. They increase dopamine levels by inhibitingthe rate at which dopamine is degraded.

Excessive muscle contraction in PD occurs when cholinergic function(which increases muscle contraction) is more powerful than dopaminergicfunction (which decreases muscle contraction). Anti-muscarinics reducecholinergic function and are therefore sometimes prescribed to bringabout more balanced muscular contraction.

Deep brain stimulation (DBS) is currently performed on patients whose PDsymptoms cannot be controlled by medication and patients for whom themedications produce unacceptable side effects. DBS is a surgicalprocedure that electrically stimulates the brain at the sites ofimplanted electrodes, most often in subthalamic nucleus, the globuspallidus internus, or the ventralis intermedius nucleus of the thalamus.The battery-powered neurostimulator to which the electrodes are attachedmay be turned off, making DBS effectively reversible, in contrast toirreversible surgical ablation (pallidotomy) at those sites of thebrain. Experimental stimulators may also turn themselves off, butstimulate only when the onset of tremors is detected by the device. Useof DBS makes it possible for the PD patients to reduce theirmedications, thereby also reducing side effects from them. Complicationsfrom DBS include those associated with the surgery itself (bleeding,reaction to anesthesia), infection, and cable breakage and migration, aswell as problems resulting from the stimulation (e.g., cognitiveproblems, numbness, double vision, etc. that cannot be corrected byadjusting stimulation parameters) [GARCIA, L., D'Alessandro, G.,Bioulac, B., Hammond, C., 2005. High-frequency stimulation inParkinson's Disease: More or less? Trends Neurosci. 28, 209-216; BITTAR,R. G. Neuromodulation for movement disorders. J. Clin. Neurosci. 13(2006), 315-318].

Vagal nerve stimulation has been performed on one PD patient who alsohad epilepsy. When the stimulation intensity was insufficient to controlepileptic seizure, the PD symptoms nevertheless improved: resting tremorresolved, bradykinesia improved and the UPDRS score decreased to from 22to 16. However, the mechanism of that improvement was not addressed.Furthermore, considering that the stimulation parameters were those thathad been optimized to treat epilepsy, it is likely that otherstimulation parameters may be more suitable for the treatment of PD [S.BOKKALA-PINNINTI, N. Pinninti and S. Jenssen. Vagus nerve stimulationeffective for focal motor seizures and focal interictal parkinsoniansymptoms—A case report. Journal of Neurology 255(2008, 2): 301-302].

Other forms of non-invasive stimulation are commonly used to treat themotor dysfunction of PD patients—repetetive transcranial magneticstimulation (rTMS) and electroconvulsive therapy (ECT). These methodsstimulate the brain directly rather stimulate the vagus nerve [F FREGNI,D K Simon, A Wu, A Pascual-Leone. Non-invasive brain stimulation forParkinson's disease: a systematic review and meta-analysis of theliterature. J Neurol Neurosurg Psychiatry 2005; 76:1614-1623;LEFAUCHEUR, J. P., Drouot, X., Von Raison, F., Menard-Lefaucheur, I.,Cesaro, P., Nguyen, J. P., 2004. Improvement of motor performance andmodulation of cortical excitability by repetitive transcranial magneticstimulation of the motor cortex in Parkinson's Disease. Clin.Neurophysiol. 115, 2530-2541]. Although the reported rTMS protocols fortreating PD were generally found to improve motor function,interpretation of their results is complicated by heterogeneity of thepatients' medication status, the use of circular versus figure-of-eightstimulation coils, stimulation at different anatomical locations, theuse of low-frequency stimulation (from 0.2 to 1 Hz) versushigh-frequency stimulation (5, 10 or 20 Hz), the use of sub-thresholdstimulation versus supra-threshold stimulation, and the use of differentmethods of assessing benefit. One such protocol demonstrated thatimproved motor performance in PD after repeated sessions of rTMS may berelated to an elevation of serum dopamine concentration [KHEDR, E. M.,Rothwell, J. C., Shawky, O. A., Ahmed, M. A., Foly, N., Hamdy, A., 2007.Dopamine levels after repetitive transcranial magnetic stimulation ofmotor cortex in patients with Parkinson's Disease: preliminary results.Mov. Disord. 2, 1046-1050]. In primates, ECT has also been shown toincrease dopaminergic neurotransmission [Anne M LANDAU, M MallarChakravarty, Campbell M Clark, Athanasios P Zis and Doris J. Doudet.Electroconvulsive Therapy Alters Dopamine Signaling in the Striatum ofNon-human Primates. Neuropsychopharmacology, (13 Oct. 2010, Epub aheadof print)].

The foregoing review of PD disclosed six novel mechanisms by whichstimulation of the vagus nerve may be used to treat PD: (1) stimulatethe vagus nerve in such a way as to prevent toxins (environmental toxin,virus, or alpha-synuclein clusters) from reaching the dorsal motornucleus of the vagus nerve, to serve as an antidote to toxins that havealready reached that location, and to prevent the pathology fromprogressing up the neuroaxis; (2) stimulate the vagus nerve in such away as to enhance the availability or effectiveness of TGF-beta or otheranti-inflammatory cytokines; (3) stimulate the vagus nerve in such a wayas to enhance the availability or effectiveness of retinoic acid; (4)stimulate the vagus nerve in such a way as to suppress the release oreffectiveness of pro-inflammatory cytokines, such as TNF-alpha, througha mechanism that is distinct from the one proposed by TRACEY andcolleagues; (5) stimulate the vagus nerve in such a way as to promotethe expression of the neurotrophic factors such as GDNF and MANE; and(6) present bright light to the patient in such a way that the lightvaries in intensity with the same waveform as the vagal nervestimulation waveform.

Embodiments of the invention in which toxins are prevented fromaffecting the dorsal motor nucleus of the vagus nerve and otherlocations along the neuroaxis are like embodiments described below fortreating PD at or near the substantia nigra, except that parameters ofthe stimulation (current, frequency, pulse width, duty cycle, etc.) arechosen in such a way as to preferentially treat the selectedneuroanatomical locations

Thus, in one embodiment of the invention, the vagus nerve in such a wayas to enhance the availability or effectiveness of TGF-beta or otheranti-inflammatory cytokines. In a related embodiment of the invention,vagal nerve stimulation promotes release of neuron-synthesized retinoicacid. In another embodiment of the invention, patients may be co-treatedwith all-trans retinoic acid (ATRA), wherein oral retinoic acid is firstadministered at a dose of 0.1 to 200 mg/sq. m, typically 20 mg/sq. m. Ifretinoic acid syndrome or other side effects are not observed in thepatient, ATRA is thereafter administered daily until vagal nervestimulation is performed, typically after one week of ATRAadministration and no more than about 45 days of ATRA administration. Itis understood that other retinoids, such as 9-cis-retinoic acid and13-cis-retinoic acid, and any other agent that biases TGF-β towards itsanti-inflammatory potential, may be substituted for ATRA, and that ifside effects are found, a reduced dose may be administered [ADAMSON, P.C., Bailey, J., Pluda, J., Poplack, D. G. Bauza, S., Murphy, R. F.,Yarchoan, R., and Balis, F. M. Pharmacokinetics of all-trans-retinoicacid administered on an intermittent schedule. J. Clin. Oncol., 13:1238-1241, 1995].

In another embodiment of the invention, the vagus nerve is stimulated insuch a way as to promote the expression of the neurotrophic factors suchas GDNF and MANF. This may be performed with or without the additionalpresentation of bright light to the patient in such a way that the lightvaries in intensity with the same waveform as the vagal nervestimulation waveform. If co-treatment with light is performed, theluminance is greater than 2500 lux, typically 7500 lux. The light sourcepreferentially produces white or short wavelength light, such as bluelight. Furthermore, output of light from the light source follows thesupply of energy to the light source, such that when power is suppliedor removed, the light rapidly appears or disappears without anysignificant lag. In the preferred embodiment, the light source compriseslight-emitting diodes (LEDs). In another embodiment of the invention,the vagus nerve in such a way as to suppress the release oreffectiveness of pro-inflammatory cytokines, such as TNF-alpha, viaanti-inflammatory cytokine, retinoic acid and neurotrophic pathways.

In the preferred embodiment of treating PD, the method stimulates thevagus nerve as indicated in FIGS. 6 and 7, using the magneticstimulation devices that are disclosed herein. The position and angularorientation of the device are adjusted about that location until thepatient perceives stimulation when current is passed through thestimulator coils. The applied current is increased gradually, first to alevel wherein the patient feels sensation from the stimulation. Thepower is then increased, but is set to a level that is less than one atwhich the patient first indicates any discomfort. Straps, harnesses, orframes are used to maintain the stimulator in position (not shown inFIG. 6 or 7). The stimulator signal may have a frequency and otherparameters that are selected to influence the therapeutic result. Forexample, a pulse width may be from about 0.01 ms to 500.0 ms, typically200 ms. The pulses may be delivered at a frequency of 0.5 to 500 Hz,typically 20 Hz. The stimulation may be performed for 1 to 200 minutes,typically for 30 minutes. Typically, the treatment is performedrepeatedly, e.g., once a month for six months. However, parameters ofthe stimulation may be varied in order to obtain a beneficial response,as indicated, for example, by the measuring levels and/or activities ofanti-inflammatory cytokines, pro-inflammatory cytokines, retinoic acid,and/or neurotrophic factors in the patient's peripheral circulationand/or in the patient's cerebrospinal fluid and/or tissue, before,during or subsequent to each treatment. A beneficial response may alsobe determined through use of standard diagnosis and treatment evaluationtools for PD, such as the Unified Parkinson's Disease Rating Scale(UPDRS).

Example Stimulation of the Vagus Nerve to Treat Multiple Sclerosis

Myelin is a dielectric material that forms a natural layer (sheath)around the axon of certain neurons. The presence of a myelin sheathincreases the speed at which electrical impulses propagate along thoseaxons, through a process known as saltation. Myelin is composed of about80% lipid (principally galactocerebroside and sphingomyelin) and about20% protein (principally myelin basic protein, myelin oligodendrocyteglycoprotein, and proteolipid protein). Myelin is formed and maintainedby Schwann cells for axons within the peripheral nervous system and byinterfascicular oligodendrocytes for axons within the central nervoussystem.

Demyelination is the loss of myelin sheaths around axons. It is theprimary cause of a category of neurodegenerative autoimmune diseases inwhich the immune system pathologically damages the nervous system bydestroying myelin. These demyelinating diseases include multiplesclerosis, acute disseminated encephalomyelitis, transverse myelitis,chronic inflammatory demyelinating polyneuropathy, Guillain-BarréSyndrome, central pontine myelinosis, leukodystrophy, and Charcot MarieTooth disease. In what follows, methods of treating multiple sclerosis(MS) are disclosed, but it is understood that the disclosure appliesalso to other demyelinating neurodegenerative diseases.

MS has no generally accepted formal definition, so that a large numberof so-called idiopathic inflammatory demyelinating diseases, also knownas borderline forms of MS, may also be treated by the disclosed methods,to the extent that autoimmunity is involved in their pathophysiology(e.g., optic-spinal MS, Devic's disease, acute disseminatedencephalomyelitis, Balo concentric sclerosis, Schilder disease, MarburgM S, tumefactive MS, pediatric and pubertal MS, and venous MS). To thatsame extent, the disclosed methods would also apply to dysmyelinationdisease, viz., diseases involving the formation of defective myelinwithout the formation of plaques, including leukodystrophies(Pelizaeus-Merzbacher disease, Canavan disease, phenylketonuria) andschizophrenia.

In MS, nerves of the brain and spinal cord not only become demyelinated,but there is also scarring (formation of scleroses, also known asplaques or lesions) of the nervous tissue, particularly in the whitematter of the brain and spinal cord, which is mainly composed of myelin.The neurons in white matter carry signals between grey matter areas ofthe central nervous system (where information processing is performed)and the rest of the body. In MS, the demyelination is found only rarelyin the peripheral nervous system [COMPSTON A and Coles A. Multiplesclerosis. Lancet 372 (9648, October 2008): 1502-1517].

The destruction of myelin takes place concomitantly with destruction ofthe oligodendrocytes that are responsible for the formation andmaintenance of myelin sheaths. As the body's own immune system attacksand damages the myelin, myelin sheaths are damaged or lost, and axonscan no longer effectively conduct signals. The inability to conductnerve signals leads to symptoms that correspond to the particularnervous tissue that has been damaged [Kenneth J. SMITH and W. I.McDonald. The pathophysiology of multiple sclerosis: the mechanismsunderlying the production of symptoms and the natural history of thedisease. Philos Trans R Soc Lond B Biol Sci. 1999 Oct. 29; 354(1390):1649-1673].

Because the demyelination can occur essentially anywhere in the whitematter of the brain and spinal cord, the MS patient can initiallyexhibit almost any neurological symptom, making an initial diagnosis ofMS difficult. Such symptoms include impairment of the central nervoussystem (fatigue, depression and moodiness, or cognitive dysfunction),visual problems (inflammation of the optic nerve, double vision, orinvoluntary eye movement), inability to articulate or swallow, muscleproblems (weakness, spasm, or lack of coordination), sensation problems(pain, insensitivity, tingling, prickliness, or numbness), bowelproblems (constipation, diarrhea, or incontinence), and urinary problems(incontinence, overactive bladder, or retention). In order of frequency,the most common initial MS symptoms are changes in sensation, visionloss, weakness, double vision, unsteady walking, and imbalance. Fifteenpercent of MS patients have multiple initial symptoms.

Following the initial symptoms, a period of months to years of remissionmay elapse. Thereafter, acute periods of relapse may occur, followed byanother remission or a gradual deterioration of neurologic function. Newsymptoms may also arise during each relapse. Progression of the diseaseis heterogeneous among MS patients, and subtypes of MS are recognized,based upon the regularity of the acute relapse and subsequent remission,the magnitude of the relapse, and the extent to which progressivedeterioration occurs between acute relapses. The most common pattern ofMS is known as relapsing-remitting MS (RRMS), in which unpredictableacute relapses may sometimes produce little or no lasting symptoms,followed by periods of no change, followed by another relapse, etc. RRMSusually begins with a clinically isolated syndrome (CIS) attack thatonly suggests MS, which develops into MS in only 30 to 70 percent of CISpatients.

Standard diagnostic tools for MS are neuroimaging, analysis ofcerebrospinal fluid, and evoked potentials. The neuroimaging includesthe use of MRI to show plaque location. The analysis of cerebrospinalfluid measures factors that would indicate the presence of chronicinflammation. The evoked potentials comprise neural stimulation thatseeks to determine the existence of a reduced neural response that wouldindicate demyelination.

Many potential triggers of MS acute relapses have been examined, butonly a few of them are often acknowledged as being likely triggers, suchas the season of the year (spring and summer), viral infection, andstress.

Epidemiological studies have also examined the likelihood that anindividual will ever have MS. More than 300 thousand individuals sufferfrom MS in North America. Worldwide, incidence of MS is significantlyhigher at locations closer to the north and south poles. Migrationstudies show that if the exposure to a higher risk environment occursbefore the age of 15 years, the migrant assumes the higher risk of theearlier environment. Epidemics of MS have been reported, most notably inthe Faroe Islands, but no causative agent has been identified.

The disease onset usually occurs in young adulthood, peaking between theages of 20 and 30, and it is 1.4 to 3.1 times more common in femalesthan males. Known genetic variations predispose an individual to haveMS, with Caucasian populations being at greater risk than Asian orAfrican populations. Although there is a tendency for MS to run infamilies, only 35% of monozygotic twins both have MS. Some environmentalfactors also increase the risk of MS, such as decreased exposure tosunlight and infection with the Epstein-Barr virus at a young age.However, there is no set of risk factors that can reliably predict theonset of MS.

It is generally recognized that MS is an autoimmune disease in which Tcells of the immune system gain entrance to the brain when theblood-brain barrier (BBB) is compromised, leading to inflammation in thebrain and spinal cord. A deficiency in uric acid is implicated incompromise of the BBB, and individuals with elevated uric acid (e.g.,gout patients) are at decreased risk of developing MS. The T cellsrecognize myelin as foreign and attack it, triggering inflammatoryprocesses and stimulating other immune cells and soluble factors such ascytokines and antibodies. Myelinating oligodendrocytes (either mature orderived from stem cells) can repair some of the demyelination, but ifthe inflammation is prolonged or frequent, the damage eventually becomesunrepairable, and a scarring (sclerosis) accumulates around thedemyelinated neurons. Furthermore, the axons of the correspondingneurons may also be damaged, probably by B-Cells of the immune system.

There is no known cure for MS. The current therapeutic practice is torelieve symptoms during and between acute attacks and to attempt toreduce the likelihood of relapses, thereby slowing progression of thedisease. Symptomatic treatment involves administration ofcorticosteroids, such as methylprednisolone, to reduce inflammationduring attacks. Other drugs are used to treat the symptoms of spasticity(baclofen, tizanidine, diazepam, clonazepam, dantrolene), optic neuritis(methylprednisolone and oral steroids), fatigue (amantadine, pemoline),pain (codeine), trigeminal neuralgia (carbamazepine), and sexualdysfunction (papaverine for men).

To prevent relapses, the following drugs are currently used: Interferonbeta-1a, interferon beta-1b, glatiramer acetate, mitoxantrone, andnatalizumab. These interferons are anti-viral proteins that may suppressthe immune system. Mitoxantrone is also an immunosuppressant thatsuppresses the proliferation of T cells and B cells. Natalizumab is amonoclonal antibody that blocks the ability of inflammatory immune cellsto attach to and pass through the cell layers lining the blood-brainbarrier, by binding to the cellular adhesion molecule a4-integrin.Glatiramer acetate is an immunomodulator drug that shifts the populationof T cells from pro-inflammatory Th1 cells to regulatory Th2 cells, byvirtue of its resemblance to myelin basic protein. Each of these drugsproduces significant side effects. For example, glatiramer acetate andthe interferon treatments produce irritation at the injection site.Interferons also produce flu-like symptoms and may cause liver damage.Mitoxantrone may cause cardiotoxicity. Natalizumab may cause multifocalleukoencephalopathy.

Experimental treatments for MS include plasma exchange, bone marrowtransplantation, potassium channel blockers to improve the conduction ofnerve impulses, the inducement of an immune attack againstmyelin-destroying T cells (vaccination and peptide therapy), proteinantigen feeding to release the protective cytokine TGF-beta,administration of TGF-beta, use of monoclonal antibodies to promoteremyelination, and various dietary therapies. Many such experimentaltreatments are motivated by experiments using an animal model of braininflammation diseases including MS, namely, experimental allergicencephalomyelitis (EAE) [HAFLER DA, Kent S C, Pietrusewicz M J, Khoury SJ, Weiner H L and Fukaura H. Oral administration of myelin inducesantigen-specific TGF-beta 1 secreting T cells in patients with multiplesclerosis. Ann N Y Acad Sci 1997; 56:120-131; MIRSHAFIEY A,Mohsenzadegan M. TGF-beta as a promising option in the treatment ofmultiple sclerosis. Neuropharmacology 56(6-7, 2009):929-36].

To date, electrical stimulation therapies have stimulated nerves of MSpatients other than the vagus nerve, primarily to treat symptoms such asurinary incontinence and spasticity [KRAUSE P, Szecsi J, Straube A. FEScycling reduces spastic muscle tone in a patient with multiplesclerosis. NeuroRehabilitation. 2007; 22(4):335-7]; P. KETELAER, G.Swartenbroekx, P. Deltenre, H. Carton and J. Gybels. Percutaneousepidural dorsal cord stimulation in multiple sclerosis. ActaNeurochirurgica 49 (1979): 95-101; L. S. ILLIS and E. M. Sedgwick.Dorsal column stimulation in multiple sclerosis. Br Med J. (1980 Aug.16); 281(6238): 518]. Electrical stimulation of the vagus nerve of MSpatients has been reported in connection with treatment of tremor anddysphagia [F. MARROSU, A. Maleci, E. Cocco, M. Puligheddu, and M. G.Marrosu. Vagal nerve stimulation effects on cerebellar tremor inmultiple sclerosis. Neurology 65 (2005): 490; F MARROSU, A Maleci, ECocco, M Puligheddu, L Barberini and M G Marrosu. Vagal nervestimulation improves cerebellar tremor and dysphagia in multiplesclerosis. Multiple Sclerosis 2007; 13: 1200-1202].

Patent application US20040249416, entitled Treatment of conditionsthrough electrical modulation of the autonomic nervous system, to YUN etal. mentions treatment of multiple sclerosis within a long list ofdiseases, in connection with stimulation of the vagus and other nerves.However, it makes no mention of modulating the activity of cytokines orneurotrophic factors.

U.S. Pat. No. 6,610,713 and U.S. Pat. No. 6,838,471, entitled Inhibitionof inflammatory cytokine production by cholinergic agonists and vagusnerve stimulation, to TRACEY, mention treatment of multiple sclerosiswithin a long list of diseases, in connection with the treatment ofinflammation through stimulation of the vagus nerve. According to thosepatents, “Inflammation and other deleterious conditions . . . are ofteninduced by proinflammatory cytokines, such as tumor necrosis factor(TNF; also known as TNF.alpha. or cachectin) . . . ” The patents goes onto state that “Proinflammatory cytokines are to be distinguished fromanti-inflammatory cytokines, . . . , which are not mediators ofinflammation.” It is clear from those patents that their objective isonly to suppress the release of proinflammatory cytokines, such asTNF-alpha. There is no mention or suggestion that the method is intendedto stimulate the release of anti-inflammatory cytokines, and in fact thetext quoted above disclaims a role for anti-inflammatory cytokines asmediators of inflammation. Those patents make a generally unjustifieddichotomy between pro- and anti-inflammatory cytokines, by indicatingthat a cytokine could be one or the other but not both. In particular,the patents make no mention of the cytokine TGF-beta, and there is nosuggestion that the role of a cytokine in regards to its pro- oranti-inflammation competence may be inherently indeterminate orindefinite unless more information is provided about the presumedphysiological environment in which the cytokine finds itself.

Treatment of multiple sclerosis is also mentioned within long lists ofdiseases in the following related applications to TRACEY and hiscolleague HUSTON, wherein stimulation of the vagus nerve is intended tosuppress the release of proinflammatory cytokines such as TNF-alpha:US20060178703, entitled Treating inflammatory disorders by electricalvagus nerve stimulation, to HUSTON et al.; US20050125044, entitledInhibition of inflammatory cytokine production by cholinergic agonistsand vagus nerve stimulation, to TRACEY; US20080249439, entitledTreatment of inflammation by non-invasive stimulation to TRACEY et al.;US20090143831, entitled Treating inflammatory disorders by stimulationof the cholinergic anti-inflammatory pathway, to HUSTON et al; US20090248097, entitled Inhibition of inflammatory cytokine production bycholinergic agonists and vagus nerve stimulation, to TRACEY et al. Thesame observations made above in connection with U.S. Pat. No. 6,610,713and U.S. Pat. No. 6,838,471 apply to those applications as well.

The present invention discloses methods for using vagal nervestimulation to suppress inflammation. However, unlike the patents andapplications to TRACEY and to HUSTON, the present invention disclosesuse of vagal nerve stimulation to increase the concentration oreffectiveness of anti-inflammatory cytokines. TRACEY et al do notconsider the modulation of anti-inflammatory cytokines to be part of thecholinergic anti-inflammatory pathway that their method of vagal nervestimulation is intended to activate. Thus, they explain that “activationof vagus nerve cholinergic signaling inhibits TNF (tumor necrosisfactor) and other proinflammatory cytokine overproduction through‘immune’ a7 nicotinic receptor-mediated mechanisms” [V. A. PAVLOV and K.J. Tracey. Controlling inflammation: the cholinergic anti-inflammatorypathway. Biochemical Society Transactions 34, (2006, 6): 1037-1040]. Incontrast, anti-inflammatory cytokines are said to be part of a different“diffusible anti-inflammatory network, which includes glucocorticoids,anti-inflammatory cytokines, and other humoral mediators” [CZURA C J,Tracey K J. Autonomic neural regulation of immunity. J Intern Med.257(2005, 2): 156-66]. Their disclaiming of a role for anti-inflammatorycytokines as mediators of inflammation following stimulation of thevagus nerve may be due to a recognition that anti-inflammatory cytokines(e.g.TGF-β) are produced constitutively while pro-inflammatory cytokines(e.g., TNF-alpha) are not, but are instead induced. However,anti-inflammatory cytokines are inducible as well as constitutive, sothat for example, an increase in the concentrations of potentiallyanti-inflammatory cytokines such as transforming growth factor-beta(TGF-β) can in fact be accomplished through stimulation of the vagusnerve [RA BAUMGARTNER, VA Deramo and MA Beaven. Constitutive andinducible mechanisms for synthesis and release of cytokines in immunecell lines. The Journal of Immunology 157 (1996, 9): 4087-4093;CORCORAN, Ciaran; Connor, Thomas J; O'Keane, Veronica; Garland, MalcolmR. The effects of vagus nerve stimulation on pro- and anti-inflammatorycytokines in humans: a preliminary report. Neuroimmunomodulation 12 (5,2005): 307-309].

In MS, the strategy of inhibiting pro-inflammatory cytokines rather thanenhancing anti-inflammatory cytokines might even be counterproductive.Thus, blocking TNF-alpha with the drug lenercept promotes andexacerbates MS attacks rather than delaying them, which might beattributable in part to the fact that TNF-alpha promotes remyelinationand the proliferation of oligodendrocytes that perform the myelination.[ANONYMOUS. TNF neutralization in MS: Results of a randomized, placebocontrolled multicenter study. Neurology 1999, 53:457; ARNETT HA, MasonJ, Marino M, Suzuki K, Matsushima G K, Ting J P. TNF alpha promotesproliferation of oligodendrocyte progenitors and remyelination. NatNeurosci 2001, 4:1116-1122].

TGF-β is currently used as an experimental treatment for multiplesclerosis [MIRSHAFIEY A, Mohsenzadegan M.TGF-beta as a promising optionin the treatment of multiple sclerosis. Neuropharmacology. 56 (2009,6-7): 929-36]. In the method disclosed herein, it is applied directly asa drug, indirectly through stimulation of the vagus nerve withoutpharmacological administration to the patient, or both directly andindirectly.

TGF-β converts undifferentiated T cells into regulatory T (Treg) cellsthat block autoimmunity. However, in the presence of interleukin-6,TGF-β also causes the differentiation of T lymphocytes intoproinflammatory IL-17 cytokine-producing T helper 17 (TH17) cells, whichpromote autoimmunity and inflammation. Thus, it is conceivable that anincrease of TGF-β levels might actually cause or exacerbateinflammation, rather than suppress it. Accordingly, a step in the methodthat is disclosed here is to deter TGF-β from realizing itspro-inflammatory potential, by selecting electrical stimulationparameters that bias the potential of TGF-β towards anti-inflammation,and/or by treating the patient with an agent such as the vitamin Ametabolite retinoic acid that is known to promote such ananti-inflammatory bias [MUCIDA D, Park Y, Kim G, Turovskaya O, Scott I,Kronenberg M, Cheroutre H. Reciprocal TH17 and regulatory T celldifferentiation mediated by retinoic acid. Science 317(2007, 5835):256-60; Sheng XIAO, Hulin Jin, Thomas Korn, Sue M. Liu, Mohamed Oukka,Bing Lim, and Vijay K. Kuchroo. Retinoic acid increases Foxp3+regulatory T cells and inhibits development of Th17 cells by enhancingTGF-β-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptorexpression. J. Immunol. 181(2008, 4): 2277-2284].

In one embodiment of the invention, endogenous retinoic acid that isproduced and released by neurons themselves is used to produce theanti-inflammatory bias. Thus, it is known that vagal nerve stimulationmay induce differentiation through release of retinoic acid that isproduced in neurons from retinaldehyde by retinaldehyde dehydrogenases,and the disclosed invention claims to induce anti-inflammatoryregulatory T cell (Treg) differentiation by this type of mechanism [vande PAVERT S A, Olivier B J, Goverse G, Vondenhoff M F, Greuter M, BekeP, Kusser K, Höpken U E, Lipp M, Niederreither K, Blomhoff R, Sitnik K,Agace W W, Randall T D, de Jonge W J, Mebius R E. Chemokine CXCL13 isessential for lymph node initiation and is induced by retinoic acid andneuronal stimulation. Nat Immunol. 2009 November; 10(11):1193-9]. It isunderstood that the methods that are disclosed here in connection withthe treatment of MS may be applied to the treatment of other diseasesthat involve inflammation, such as post-operative ileus.

Thus, the present invention comprises a pro-anti-inflammatory mechanismbecause it biases the competence of TGF-beta towards that of ananti-inflammatory cytokine. An increase in the concentrations ofpotentially anti-inflammatory cytokines such as TGF-β can also beaccomplished through stimulation of the vagus nerve, which is also apro-anti-inflammatory mechanism when TGF-β is biases towardsanti-inflammation [CORCORAN, Ciaran; Connor, Thomas J; O'Keane,Veronica; Garland, Malcolm R. The effects of vagus nerve stimulation onpro- and anti-inflammatory cytokines in humans: a preliminary report.Neuroimmunomodulation 12 (5, 2005): 307-309]. As mentioned above,inhibiting the pro-inflammatory cytokine TNF-alpha is considered to becounterproductive in MS patients, there may be circumstances in whichthe inhibition of other pro-inflammatory cytokines may be usefultherapeutically. In that case, stimulation of the vagus nerve in anattempt to produce the anti-pro-inflammatory response advocated byTRACEY and colleagues may be attempted. However, ananti-pro-inflammatory response may be produced by another mechanisminvolving stimulation of the vagus nerve, because as indicated above,vagal nerve stimulation may result in the release of retinoic acid, andthe retinoic acid itself inhibits pro-inflammatory cytokines [MalcolmMaden. Retinoic acid in the development, regeneration and maintenance ofthe nervous system. Nature Reviews Neuroscience 8 (2007), 755-765].

The potentially anti-inflammatory cytokine TGF-beta is a member of theTGF-beta superfamily of neurotrophic factors. Neurotrophic factors serveas growth factors for the development, maintenance, repair, and survivalof specific neuronal populations, acting via retrograde signaling fromtarget neurons by paracrine and autocrine mechanisms. Other neurotrophicfactors also promote the survival of neurons during neurodegeneration.These include members of the nerve growth factor (NGF) superfamily, theglial-cell-line-derived neurotrophic factor (GDNF) family, the neurokinesuperfamily, and non-neuronal growth factors such as the insulin-likegrowth factors (IGF) family. However, major problems in using suchneurotrophic factors for therapy are their inability to cross theblood-brain-barrier, adverse effects resulting from binding to thereceptor in other organs of the body and their low diffusion rate[Yossef S. Levy, Yossi Gilgun-Sherki, Eldad Melamed and Daniel Offen.Therapeutic Potential of Neurotrophic Factors in NeurodegenerativeDiseases. Biodrugs 2005; 19 (2): 97-127].

It is known that vagal nerve stimulation and transcranial magneticstimulation can increase the levels of at least one neurotrophic factorin the brain, brain-derived neurotrophic factor (BDNF), which has beenstudied extensively in connection with the treatment of depression[Follesa P, Biggio F, Gorini G, Caria S, Talani G, Dazzi L, PulighedduM, Marrosu F, Biggio G. Vagus nerve stimulation increases norepinephrineconcentration and the gene expression of BDNF and bFGF in the rat brain.Brain Research 1179 (2007): 28-34; Biggio F, Gorini G, Utzeri C, 011a P,Marrosu F, Mocchetti I, Follesa P. Chronic vagus nerve stimulationinduces neuronal plasticity in the rat hippocampus. Int JNeuropsychopharmacol. 12(9, 2009):1209-21; Roberta Zanardini, AnnaGazzoli, Mariacarla Ventriglia, Jorge Perez, Stefano Bignotti, PaoloMaria Rossini, Massimo Gennarelli, Luisella Bocchio-Chiavetto. Effect ofrepetitive transcranial magnetic stimulation on serum brain derivedneurotrophic factor in drug resistant depressed patients. Journal ofAffective Disorders 91 (2006) 83-86]. It has never been proposed beforethe present disclosure that vagal nerve stimulation may be utilized toincrease BDNF levels in MS patients. BDNF is known to reduce clinicalinflammation and cell death in an animal model of MS [Makar T K, TrislerD, Sura K T, Sultana S, Patel N, Bever C T. Brain derived neurotrophicfactor treatment reduces inflammation and apoptosis in experimentalallergic encephalomyelitis. J Neurol Sci. 270(1-2, 2008):70-6]. Vagalnerve stimulation may likewise promote the expression of otherbeneficial neurotrophic factors as well, which circumvents the problemof blood-brain barrier blockage by being induced through vagal nervestimulation. Patent application US20100280562, entitled Biomarkers formonitoring treatment of neuropsychiatric diseases, to PI et al,disclosed the measurement of BDNF following vagal nerve stimulation.However, that application is concerned with the search for biomarkersinvolving the levels of BDNF, rather than a method for treating aneurodegenerative disease using vagal nerve stimulation.

The foregoing review of MS disclosed four novel mechanisms by whichstimulation of the vagus nerve may be used to treat MS: (1) stimulatethe vagus nerve in such a way as to enhance the availability oreffectiveness of TGF-beta or other anti-inflammatory cytokines; (2)stimulate the vagus nerve in such a way as to enhance the availabilityor effectiveness of retinoic acid; (3) stimulate the vagus nerve in sucha way as to suppress the release or effectiveness of pro-inflammatorycytokines, through a mechanism that is distinct from the one proposed byTRACEY and colleagues; (4) stimulate the vagus nerve in such a way as topromote the expression of the neurotrophic factors such as BDNF.

In one embodiment of the invention, patients may be co-treated withall-trans retinoic acid (ATRA), wherein oral retinoic acid is firstadministered at a dose of 0.1 to 200 mg/sq. m, typically 20 mg/sq. m. Ifretinoic acid syndrome or other side effects are not observed in thepatient, ATRA is thereafter administered daily until vagal nervestimulation is performed, typically after one week of ATRAadministration and no more than about 45 days of ATRA administration. Itis understood that other retinoids, such as 9-cis-retinoic acid and13-cis-retinoic acid, and any other agent that biases TGF-β towards itsanti-inflammatory potential, may be substituted for ATRA, and that ifside effects are found, a reduced dose may be administered [ADAMSON, P.C., Bailey, J., Pluda, J., Poplack, D. G. Bauza, S., Murphy, R. F.,Yarchoan, R., and Balis, F. M. Pharmacokinetics of all-trans-retinoicacid administered on an intermittent schedule. J. Clin. Oncol., 13:1238-1241, 1995].

In another embodiment of the invention, vagal nerve stimulation itselfpromotes release of neuron-synthesized retinoic acid, thereby inducingthe differentiation undifferentiated T cells into anti-inflammatoryregulatory T cells (Treg) in the presence of the cytokine TGF-beta. Inyet another embodiment of the invention, both endogenous (induced byvagal nerve stimulation) and exogenous retinoic acid (administered as adrug) are used to induce differentiation of undifferentiated T cellsinto regulatory T (Treg) cells. Other aspects of the invention are thatTGF-beta itself may be induced by the vagal nerve stimulation, therelease of proinflammatory cytokines such as TNF-alpha may be blocked bythe vagal nerve stimulation, and neurotrophic factors such as BDNF maybe induced by the vagal nerve stimulation.

In the preferred embodiment of treating MS, the method stimulates thevagus nerve as indicated in FIGS. 6 and 7, using the magneticstimulation devices that are disclosed herein. The position and angularorientation of the device are adjusted about that location until thepatient perceives stimulation when current is passed through thestimulator coils. The applied current is increased gradually, first to alevel wherein the patient feels sensation from the stimulation. Thepower is then increased, but is set to a level that is less than one atwhich the patient first indicates any discomfort. Straps, harnesses, orframes are used to maintain the stimulator in position (not shown inFIG. 6 or 7). The stimulator signal may have a frequency and otherparameters that are selected to influence the therapeutic result. Forexample, a pulse width may be from about 0.01 ms to 500.0 ms, typically200 ms. The pulses may be delivered at a frequency of 0.5 to 500 Hz,typically 20 Hz. The stimulation may be performed for 1 to 200 minutes,typically for 30 minutes. Typically, the treatment is performedrepeatedly, e.g., once a month for six months or throughout a period ofremission. However, parameters of the stimulation may be varied in orderto obtain a beneficial response, as indicated, for example, by measuringlevels and/or activities of TGF-β or other anti-inflammatory cytokines,pro-inflammatory cytokines, and/or neurotrophic factors such as BDNF inthe patient's peripheral circulation and/or in the patient'scerebrospinal fluid, before, during and subsequent to each treatment. Abeneficial response may also be determined through use of standarddiagnostic tools for MS, including neuroimaging, analysis ofcerebrospinal fluid, and evoked potentials. The treatment is primarilyintended to prevent MS relapses during remission, but it may also beadministered to patients while a MS relapse is in progress, so as tohasten entry into remission.

Example Stimulation of the Vagus Nerve to Treat Postoperative CognitiveDysfunction and/or Postoperative Delirium

Postoperative cognitive dysfunction (POCD) is a loss in cognitivefunction after surgery. The loss may include memory, the ability tolearn, the ability to concentrate, and/or the ability to reason andcomprehend. The cognitive decline may be subtle, such that psychologicaltesting is needed to detect it, or it may be profound and obvious.

POCD does not refer to delirium that may occur immediately aftersurgery, but instead refers to cognitive loss that may persist weeks,months, or permanently after the surgery. However, postoperativecognitive dysfunction and postoperative delirium (POD) are not mutuallyexclusive. They may in fact have risk factors, mechanisms, and treatmentoptions in common. Accordingly, background information pertaining to PODis presented below, after first discussing POCD and disclosing methodsfor treating POCD.

A limited number of studies have been conducted to evaluate whethercertain demographic populations are at higher risk to suffer from POCD,whether the risk is contingent on the type of surgery, whether the riskdepends on the anesthesia that was used, how the medical condition ofthe patient prior to the surgery influences the risk, whether drugsensitivity is involved, and whether these variables influence theduration of the POCD, its preventability, or its treatability. Elderlypatients are at greatest risk for developing POCD. A low level ofeducation predisposes a risk of POCD. Patients undergoing cardiacsurgery are at greatest risk, especially those with progressiveatherosclerosis. However, major surgery in general poses a greater riskof developing POCD than minor surgery. The incidence of prolonged POCDis apparently similar regardless of the anesthetic technique used,suggesting that nonanesthetic factors are likely to be important.However, use of regional anesthesia decreases the incidence of POCDearly after surgery. [Lars S. RASMUSSEN. Postoperative cognitivedysfunction: Incidence and prevention. Best Practice & Research ClinicalAnesthesiology 20(2006, No. 2): 315-330; Ola A. SELNES and Guy M.McKhann. Neurocognitive Complications after Coronary Artery BypassSurgery. Ann Neurol 2005; 57:615-621; Ramesh RAMAIAH and Arthur M. Lam.Postoperative Cognitive Dysfunction in the Elderly. Anesthesiology Clin27 (2009): 485-496; Anne-Mette SAUËR, Cornelis Kalkman and Diederik vanDijk. Postoperative cognitive decline. J Anesth (2009) 23:256-259].

The pathophysiology of POCD has been investigated in view of the aboveclinical findings and in the context of cellular responses to surgery ingeneral [Niamh Ni CHOILEAIN and H. Paul Redmond. Cell response tosurgery. Arch Surg 2006; 141:1132-40; XIE GL, Zhang W, Chang Y Z, Chu QJ. Relationship between perioperative inflammatory response andpostoperative cognitive dysfunction in the elderly. Med Hypotheses 2009;73:402-3; HU Z, Ou Y, Duan K, Jiang X. Inflammation: a bridge betweenpostoperative cognitive dysfunction and Alzheimer's disease. MedHypotheses. 2010 April; 74(4):722-4].

Although the cause of POCD appears to be multifactorial, the response ofthe body to the surgery itself appears to be a primary contributingfactor. This is because decreased surgical trauma is associated with adecreased risk of POCD, and the stress of surgery triggers aninflammatory response with release of cytokines that may be responsiblefor changes in brain function and recovery. Furthermore, a correlationhas been observed in patients' interleukin-6, cortisol and latefunctional recovery. Animal experiments also indicate that there is arelation between cytokine-mediated inflammation and POCD [Y WAN, J Xu, DMa, Y Zeng, M Cibelli, M Maze. Postoperative impairment of cognitivefunction in rats: a possible role for cytokine-mediated inflammation inthe hippocampus. Anesthesiology 2007; 106:436-43].

There is currently no generally agreed-upon treatment for POCD. Primaryprevention by providing good oxygenation and cerebral perfusion duringsurgery, and adequate analgesia and emotional support after surgery havebeen suggested, including the use of occupational therapy andbiofeedback. Medical conditions that could also contribute to POCDshould also be treated, such as hypothyroidism. Otherwise, there are fewtreatment options. XIONG et al suggested that transcutaneous stimulationof the vagus nerve may attenuate the inflammatory response that appearsto be associated with POCD. Their suggestion was that the stimulation betranscutaneous because implantation of a vagal nerve stimulator bysurgery may exacerbate the very surgery-induced problem that thestimulation is intended to treat. [XIONG J, Xue F S, Liu J H, Xu Y C,Liao X, Zhang Y M, Wang W L, Li S. Transcutaneous vagus nervestimulation may attenuate postoperative cognitive dysfunction in elderlypatients. Medical Hypotheses 73 (2009) 938-941].

However, the site of transcutaneous vagal stimulation that XIONG et alsuggest is the external auditory canal. This may not be as effective asstimulating at the site where vagus nerve stimulators are ordinarilyimplanted, namely, in the neck. Furthermore, XIONG et al do not suggeststimulation parameters that should be used. Accordingly, methods aredisclosed here to better treat POCD patients. The methods counteractinflammation by any of the mechanisms shown in FIG. 8.

In the preferred embodiment, the method stimulates the vagus nerve inthe neck as indicated in FIGS. 6 and 7, using the magnetic stimulationdevices that are disclosed herein. The position is adjusted about thatlocation, and the angular orientation of the device is also rotatedabout that location, until the patient perceives stimulation whencurrent is passed through the stimulator coils. The applied current isincreased gradually, first to a level wherein the patient feelssensation from the stimulation. The power is then increased, but is setto a level that is less than one at which the patient first indicatesany discomfort. Straps, harnesses, or frames are used to maintain thestimulator in position (not shown in FIG. 6 or 7). The stimulator signalmay have a frequency and other parameters that are selected to influencethe therapeutic result. For example, a pulse width may be from about0.01 ms to 500.0 ms, typically 200 ms. The pulses may be delivered at afrequency of 0.5 to 500 Hz., typically 20 Hz. The stimulation may beperformed for 1 to 200 minutes, typically for 30 minutes. Typically, thetreatment is performed repeatedly, e.g., once a week for six months.However, parameters of the stimulation may be varied in order to obtaina beneficial response, as indicated, for example, by the measurement oflevels and/or activities of TGF-beta, neurotrophic factors, retinoicacid, and/or TNF-alpha in the patient's peripheral circulation and/or inthe patient's cerebrospinal fluid, during and subsequent to eachtreatment, or by psychological evaluation of the extent of the patient'scognitive dysfunction.

If a patient experiences postoperative delirium before experiencingPOCD, the disclosed method of treatment is initially somewhat different,as now described. According to the American Psychiatric Associationdiagnostic manual (DSM-IV-TR), delirium is a potentially reversiblestate of acute brain failure with disturbance of consciousnessaccompanied by cognitive deficits that cannot be accounted for by pastor evolving dementia and is associated with evidence of physiologicaldisturbance owing to a medical condition. It is characterized by theinability to focus attention, disorientation that is not attributable todementia, sleep disturbance, and sometimes disruptive behavior. However,in the elderly, the earliest signs of delirium may be withdrawal ratherthan agitation.

Postoperative delirium (POD) is delirium that develops acutely aftersurgery, usually within hours to days, and its severity often fluctuatesduring the course of the day. The physiological disturbance with whichthe delirium is associated is the surgery itself. The time-course of PODis typically a shock phase of several hours after surgery in which thepatient is hypometabolic, followed by a hypermetabolic inflammatoryphase that ordinarily peaks two days after surgery, followed by a returnto normal within a week. If the problem does not resolve itselfcompletely within this time frame, the patient may be considered tosuffer from postoperative cognitive dysfunction (POCD) rather than POD.

POD occurs in 10 to 50% of postoperative patients and in 80% of elderlypatients who require intensive care. Patients undergoing cardiovascular,major abdominal and orthopedic surgery are most prone to develop POD.Twenty five percent of elderly patients who exhibit POD die within sixmonths.

Factors that may predispose to the development of POD include exposureto toxins (including CNS-active drugs and alcohol abuse), infection,inflammation (resulting, for example, from autoimmune disease), traumaincluding postoperative trauma, decreased cardiac output and/or oxygensaturation, vascular disease, metabolic derangement, vitamin deficiency,central nervous system states such as epilepsy, hydrocephalus, andcentral nervous system lesions. Prevention or treatment of POD willinitially involve the identification, management and/or elimination ofsuch predisposing factors [Yu-Ling CHANG, Yun-Fang Tsai, Pyng-Jing Lin,Min-Chi Chen, and Chia-Yih Liu. Prevalence and risk factors forpostoperative delirium in a cardiovascular intensive care unit. AmericanJournal of Critical Care. 2008; 17:567-575; RUDRA A, Chatterjee S,Kirtania J, Sengupta S, Moitra G, Sirohia S, Wankhade R, Banerjee S.Postoperative delirium. Indian J Crit Care Med 2006; 10:235-40].

Behavior suggestive of delirium includes the inability to focusattention, incoherent speech, hallucination, withdrawal orhypervigilance. In contrast to dementia, such behavior with POD mayfluctuate significantly over the course of even a few hours. TheDelirium Symptom Interview, the Confusion Assessment Method, theDelirium Scale, the Delirium Rating Scale and the Memorial DeliriumAssessment Scale are formal psychological measurements that are usefulfor forming an initial diagnosis of patients who are not agitated.

The antidopaminergic drug haloperidol is often administeredintravenously to counter the neuronal dysfunction associated withdelirium, especially when agitation is present. This is becausepsychotic fear in delirium may originate in the amygdala, whichabnormally excites dopamine subpopulations that project to limbic areasand to cognitive regions of the cortex and striatum. Thus, fear indelirium requires the use of dopamine-blocking neuroleptics rather thanbenzodiazepines. However, careful monitoring of the cardiovascularsystem is necessary because of the potential for ventricular arrhythmiafollowing use of haloperidol [Gregory L. FRICCHIONE, Shamim H. Nejad,Justin A. Esses, Thomas J. Cummings, Jr., John Querques, Ned H. Cassem,and George B. Murray. Postoperative Delirium. Am J Psychiatry 165 (7,July 2008): 803-812].

POD is thought to arise initially because leukocytes adhere tosurgically damaged endothelial cells and become activated. Theirdegranulation releases free oxygen radicals and enzymes, which in turnleads to endothelial cell membrane destruction, loosening ofintercellular tights, extravascular fluid shift, and formation ofperivascular edema. The immune response in the brain is amplified inpatients whose predisposing factors cause the blood-brain barrier tohave compromised integrity [James L. RUDOLPH, Basel Ramlawi, George A.Kuchel, Janet E. McElhaney, Dongxu Xie, Frank W. Sellke, Kamal Khabbaz,Sue E. Levkoff, and Edward R. Marcantonio. Chemokines are Associatedwith Delirium after Cardiac Surgery. J Gerontol A Biol Sci Med Sci. 2008February; 63(2): 184-189]. The edema in turn produces longer diffusiondistance for oxygen to reach nerve cells. Furthermore, the blood flow inindividual capillaries may become disrupted. Synthesis and release ofthe neurotransmitter acetylcholine (ACH) is particularly sensitive tothe resulting hypoxia, especially in the elderly.

Such oxidative stress may produce localized neuronal dysfunction in thehippocampus and amygdala, which subsequently progresses to dysfunctionin the brainstem, gray matter, and cerebellum. The neuronal dysfunctionis associated with neurotransmitter disequilibrium corresponding todecreased acetylcholine and GABA, as well as increased dopamine andglutamate. That neurotransmitter dysfunction ultimately produces thesymptoms of delirium. Thus, the decreased ACH leads to a relative excessof dopaminergic transmission, wherein the amygdala projects to dopaminesubpopulations in limbic and cognitive areas of the brain that producefear in delirious patients. [Martin Hala. Pathophysiology ofpostoperative delirium: Systemic inflammation as a response to surgicaltrauma causes diffuse microcirculatory impairment. Medical Hypotheses(2007) 68, 194-196]. Accordingly, applicants disclose herein a methodfor preventing or minimizing excessive development of the perioperativeinflammation that leads to POD. The method is like that used to treatPOCD in that involves stimulation of the vagus nerve in the neck toincrease reserve levels of the neurotransmitter acetylcholine, in such away as to promote a normal balance of neurotransmitter levels. However,the method differs from that used to treat POCD in that the parametersof the stimulation are selected to specifically promote normalneurotransmitter levels in the amygdala and in the limbic and cognitiveareas of the brain to which the amygdala projects. Vagal afferentstraverse the brainstem in the solitary tract, with terminating synapsesparticularly located in the nucleus of the tractus solitarius (NTS). TheNTS projects to a wide variety of structures including the para brachialnucleus, which in turn projects to the hypothalamus, the thalamus, theamygdala, the anterior insular, and infralimbic cortex, lateralprefrontal cortex, and other cortical regions. Through its projection tothe amygdala, the NTS gains access to amygdala-hippocampus-entorhinalcortex pathways of the limbic system. Thus, the disclosed treatment ofPOD by vagal nerve stimulation uses parameters (intensity, pulse-width,frequency, duty cycle, etc.) that preferentially activate the limbicsystem via the amygdala [Jeong-Ho CHAE, Ziad Nahas, Mikhail Lomarev,Stewart Denslow, Jeffrey P. Lorberbaum, Daryl E. Bohning, Mark S.George. A review of functional neuroimaging studies of vagus nervestimulation (VNS). Journal of Psychiatric Research 37 (2003) 443-455] orby other routes [G. C. Albert, C. M. Cook, F. S. Prato, A. W. Thomas.Deep brain stimulation, vagal nerve stimulation and transcranialstimulation: An overview of stimulation parameters and neurotransmitterrelease. Neuroscience and Biobehavioral Reviews 33 (2009) 1042 1060].

In the preferred embodiment, the method stimulates the vagus nerve inthe neck as indicated in FIGS. 6 and 7, using the magnetic stimulationdevices that are disclosed herein. Any of the anti-inflammatorymechanisms shown in FIG. 8 may be induced by the stimulation.

The position of the device is adjusted and the angular orientation ofthe device is also rotated about an initial location, until the patientperceives stimulation when current is passed through the stimulatorcoils. The applied current is increased gradually, first to a levelwherein the patient feels sensation from the stimulation. The power isthen increased, but is set to a level that is less than one at which thepatient first indicates any discomfort. Straps, harnesses, or frames areused to maintain the stimulator in position (not shown in FIG. 6 or 7).The stimulator signal may have a frequency and other parameters that areselected to influence the therapeutic result. For example, a pulse widthmay be from about 0.01 ms to 500.0 ms, typically 200 ms. The pulses maybe delivered at a frequency of 0.5 to 500 Hz., typically 20 Hz. Thestimulation may be performed for 1 to 200 minutes, typically for 30minutes. Typically, the treatment is performed repeatedly, e.g., beforesurgery, and daily after surgery. However, parameters of the stimulationmay be varied in order to obtain a beneficial response, as indicated,for example, by the measurement of levels and/or activities of TGF-beta,neurotrophic factors, retinoic acid, and/or TNF-alpha in the patient'speripheral circulation and/or in the patient's cerebrospinal fluid,during and subsequent to each treatment, or by psychological evaluationof the extent of the patient's delirium.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

1. A method for treating a neurodegenerative disorder in a patientcomprising: applying energy to the patient to generate an electricalimpulse at or near a selected nerve within the patient; and modulatingthe energy such that the electrical impulse is sufficient to increase anactivity of anti-inflammatory cytokines in the patient to inhibitinflammation and treat the neurodegenerative disorder.
 2. The method ofclaim 1 wherein the applying energy is carried out by transcutaneouslypassing an electrical current through an outer skin surface of thepatient.
 3. The method of claim 1 wherein the applying energy is carriedout by generating a magnetic field exterior to the patient sufficient toinduce an electrical impulse at or near the selected nerve within thepatient.
 4. The method of claim 1 wherein the electrical impulse issufficient to stimulate nerve fibers that control or mediate activity ofa neurotrophic factor.
 5. The method of claim 1 wherein theneurodegenerative disease is selected from a group comprisingAlzheimer's disease, Parkinson's disease, multiple sclerosis,postoperative cognitive dysfunction or postoperative delirium.
 6. Themethod of claim 1 wherein the selected nerve is a vagus nerve.
 7. Themethod of claim 6 wherein the selected nerve is a right branch of thevagus nerve.
 8. The method of claim 4 wherein the neurotrophic factor isa member of the transforming growth factor (TGF) beta superfamily ofneurotrophic factors.
 9. The method of claim 4 wherein the neurotrophicfactor is a member of the nerve growth factor superfamily, the neurokinesuperfamily, or the insulin-like family of non-neuronal growth factors.10. The method of claim 4 wherein the neurotrophic factor is a member ofthe same family as nerve growth factor (NGF), glial-cell-line-derivedneurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), ormesencephalic astrocyte-derived neurotrophic factor (MANF).
 11. Themethod of claim 1 wherein the electrical impulse is sufficient toinhibit release of a pro-inflammatory cytokine.
 12. The method of claim11 wherein the pro-inflammatory cytokine is tumor necrosis factor(TNF)-alpha.
 13. The method of claim 1 wherein the applying energy iscarried out by: generating a time-varying magnetic field that is locatedentirely outside of the patient; shaping an electric field that isinduced by said magnetic field; and conducting an electric current thatis induced by said magnetic field through an outer skin surface of thepatient to modulate the selected nerve.
 14. The method of claim 1wherein the selected nerve is at least approximately 1-2 cm below anouter skin surface of the patient.
 15. The method of claim 14 whereinthe generating comprises generating the time-varying magnetic fieldwithin a first enclosed coil.
 16. The method of claim 1 wherein thegenerating comprises generating an electric current and transmitting theelectric current to the vagus nerve of the patient.
 17. An apparatus forapplying energy transcutaneously to a target region within a patientwith a neurodegenerative disorder, comprising: an enclosure; and a powersource housed within the enclosure and configured to generate an energyfield that is sufficient to generate an electrical impulse at or nearthe target region sufficient to modulate activity of a selected nerve atthe target region to increase an activity of anti-inflammatory cytokinesin the patient and treat the neurodegenerative disorder.
 18. Theapparatus of claim 17 wherein the power source is configured to transmitthe energy field transcutaneously through an outer skin surface of thepatient to the selected nerve.
 19. The apparatus of claim 17 furthercomprising a conduction medium, wherein the power energy is configuredto generate an electric field that induces an electrical currentsufficient to pass through the outer skin surface of the patient. 20.The apparatus set forth in claim 17 wherein the electrical impulse issufficient to inhibit release of a pro-inflammatory cytokine.
 21. Theapparatus set forth in claim 20 wherein the pro-inflammatory cytokine istumor necrosis factor (TNF)-alpha.
 22. The apparatus set forth in claim20 wherein the cytokine is tumor growth factor (TGF)-beta.
 23. Theapparatus set forth in claim 22 wherein a retinoid or a component of aretinoic acid signaling system biases the competence of the cytokinetowards anti-inflammation.
 24. The apparatus set forth in claim 17wherein the electrical impulse is sufficient to enhanceanti-inflammatory activity of a neurotrophic factor.
 25. The apparatusset forth in claim 24 wherein the neurotrophic factor is a member of thetransforming growth factor (TGF)-beta superfamily of neurotrophicfactors, the nerve growth factor superfamily of neurotrophic factors,the neurokine superfamily of neurotrophic factors, or the insulin-likefamily of non-neuronal growth factors.
 26. The apparatus set forth inclaim 17 wherein the selected nerve is a vagus nerve of the patient. 27.The apparatus set forth in claim 19 wherein the electrical field has anamplitude of greater than about 10 V/m.
 28. The apparatus set forth inclaim 19 wherein the electrical field has a gradient of greater thanabout 2 V/m/mm.
 29. The apparatus set forth in claim 17 wherein theenergy field comprises bursts of pulses with a frequency of about 5 Hzto about 100 Hz.
 30. The apparatus set forth in claim 29 wherein theenergy field comprises bursts of from 1 to 20 pulses with each pulseabout 50-1000 microseconds in duration.
 31. The apparatus of claim 17wherein the power source is configured to generate an electric currentand to transmit the electric current through an outer skin surface ofthe patient to the selected nerve.
 32. The apparatus set forth in claim17 wherein the neurodegenerative disease is Alzheimer's disease,Parkinson's disease, multiple sclerosis, postoperative cognitivedysfunction or postoperative.